Equilibrium in [18F]fallypride PET

Post-Processing via Cation Exchange Cartridges: Versatile Options

New 68Ge/68Ga radionuclide generators provide the positron emitter 68Ga (T½ = 67.7 min) as an easily available and relatively inexpensive source of a PET nuclide for labeling of interesting targeting vectors. However, currently available “ionic” 68Ge/68Ga radionuclide generators are not necessarily optimized for the routine synthesis of 68Ga-labeled radiopharmaceuticals in a clinical environment. Post-processing of 68Ge/68Ga generators using cation exchange resins provides chemically and radiochemically pure 68Ga with 97±2% within less than 4 min, with 68Ge almost completely removed, and ready for online labeling. This simple, fast, and efficient technology can be extended for new applicati…

Efficient alkali iodide promoted 18F-fluoroethylations with 2-[18F]fluoroethyl tosylate and 1-bromo-2-[18F]fluoroethane

Abstract Radiochemical 18 F-fluorination yields of several compounds using the secondary labelling precursors 2-[ 18 F]fluoroethyl tosylate ([ 18 F]FETos) and 1-bromo-2-[ 18 F]fluoroethane ([ 18 F]BFE) could be considerably enhanced by the addition of an alkali iodide. The radiochemical yield of [ 18 F]fluoroethyl choline for example could be doubled with [ 18 F]BFE and increased from 13% to ≈80% with [ 18 F]FETos. By addition of alkali iodide to the precursor, the 18 F-fluoroethylation yields of established radiopharmaceuticals, especially in the case of automated syntheses, could be significantly increased without major changes of the reaction conditions.

Copper-catalyzed click reactions: quantification of retained copper using 64Cu-spiked Cu(I), exemplified for CuAAC reactions on liposomes

Abstract The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) is a powerful, highly reliable and selective reaction which allows for a rapid synthesis in high yields and under mild conditions (pH, temperature). However, the cytotoxicity of copper requires its complete removal prior to an application in vivo. This is an issue especially when it comes to CuAAC reactions on macromolecular structures or drug delivery systems, as copper might be retained by these systems. Thus, a quantification of the final copper content of these systems is inevitable, which we exemplified for a CuAAC reaction on liposomes using 64Cu-spiked Cu(I). In this respect, a Cu(II) nitrate solution was irradiated at t…

Synthesis and evaluation of (S)-2-(2-[18F]fluoroethoxy)-4-([3-methyl-1-(2-piperidin-1-yl-phenyl)-butyl-carbamoyl]-methyl)-benzoic acid ([18F]repaglinide): a promising radioligand for quantification of pancreatic β-cell mass with positron emission tomography (PET)

18F-labeled non-sulfonylurea hypoglycemic agent (S)-2-(2-[(18)F]fluoroethoxy)-4-((3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl)-methyl)-benzoic acid ([(18)F]repaglinide), a derivative of the sulfonylurea-receptor (SUR) ligand repaglinide, was synthesized as a potential tracer for the non-invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta-cells by positron emission tomography (PET) in the context of type 1 and type 2 diabetes. [(18)F]Repaglinide could be obtained in an overall radiochemical yield (RCY) of 20% after 135 min with a radiochemical purity higher than 98% applying the secondary labeling precursor 2-[(18)F]fluoroethyltosylate. Specific activity w…

Predicting the in vivo release from a liposomal formulation by IVIVC and non-invasive positron emission tomography imaging

This study aimed to predict the in vivo performance from the in vitro release of a low-molecular weight model compound, [(18)F]-2-fluoro-2-deoxy-d-glucose ([(18)F]FDG), from liposomes and by means of positron emission tomography (PET). Liposomes composed of hydrogenated phosphatidylcholine (HPC) were prepared by a freeze-thaw method. Particle size distribution was measured by dynamic light scattering (DLS). In vitro release was examined with a dispersion method detecting the radioactivity of [(18)F]FDG. In vivo release of [(18)F]FDG, following i.p. injection of the liposomes in rats, was determined by using a Micro-PET scanner. Convolution was performed to predict the in vivo profiles from …

In vivo Evaluation of [225Ac]Ac-DOTAZOL for α-Therapy of Bone Metastases

Background Conjugates of bisphosphonates with macrocyclic chelators possess high potential in bone targeted radionuclide imaging and therapy. DOTAZOL, zoledronic acid conjugated to DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), demonstrated promising results in vivo in small animals as well as in first patient applications using 68Ga for diagnosis via PET and the lowenergy β-emitter 177Lu for therapy of painful bone metastases. In consideration of the fact that targeted α-therapy probably offers various advantages over the use of β--emitters, the 225Ac-labelled derivative [225Ac]Ac-DOTAZOL was synthesized and evaluated in vivo. Here, we report on radiolabelling and biodist…

Total synthesis and evaluation of [18F]MHMZ.

Radiochemical labeling of MDL 105725 using the secondary labeling precursor 2-[(18)F]fluoroethyltosylate ([(18)F]FETos) was carried out in yields of approximately 90% synthesizing [(18)F]MHMZ in a specific activity of approximately 50MBq/nmol with a starting activity of approximately 3GBq. Overall radiochemical yield including [(18)F]FETos synthon synthesis, [(18)F]fluoroalkylation and preparing the injectable [(18)F]MHMZ solution was 42% within a synthesis time of approximately 100 min. The novel compound showed excellent specific binding to the 5-HT(2A) receptor (K(i)=9.0 nM) in vitro and promising in vivo characteristics.

Synthesis and in vitro evaluation of (S)-2-([11C]methoxy)-4-[3-methyl-1-(2-piperidine-1-yl-phenyl)-butyl-carbamoyl]-benzoic acid ([11C]methoxy-repaglinide): a potential beta-cell imaging agent.

The 11 C-labeled sulfonylurea receptor 1 (SUR1) ligand (S)-2-(( 11 C)methoxy)-4-(3-methyl-1-(2-piperidine-1-yl-phenyl)- butyl-carbamoyl)-benzoic acid (( 11 C)methoxy-repaglinide) was synthesized in an overall radiochemical yield of 35% after 55 min with a radiochemical purity higher than 99%. This compound is considered for the noninvasive investigation of the SUR1 receptor status of pancreatic b-cells by positron emission tomography (PET) in the context of type 1 and type 2 diabetes. The specific activity was 40-70 GBq/lmol. In vitro testing of the nonradioactive methoxy-repaglinide was performed to characterize the affinity for binding to the human SUR1 isoform. Methoxy-repaglinide induce…

Efficient synthesis of 2-bromo-1-[18F]fluoroethane and its application in the automated preparation of 18F-fluoroethylated compounds

An efficient synthesis of 2-bromo-1-[18F]fluoroethane from commercially available 1,2-dibromoethane and its integration into an automated preparation device was developed for the routine synthesis of 18F-fluoroethylated compounds. The 1,2-dibromoethane was reacted with the [18F]fluoride/Kryptofix 2.2.2./carbonate complex in acetonitrile at 70 degrees C for 3 min resulting in 60-70% radiochemical yields. The crude reaction mixture was diluted with water, loaded on a LiChrolute EN-cartridge, eluted with acetonitrile and passed through an AluminaB-cartridge. This method provides 2-bromo-1-[18F]fluoroethane with 98% radiochemical purity and <0.1 micromol of 1,2-dibromoethane within 10 min, thus…

Syntheses of novelN-([18F]fluoroalkyl)-N-nitroso-4-methyl-benzenesulfonamides and decomposition studies of corresponding19F- and bromo-analogues: potential new compounds for the18F-labelling of radiopharmaceuticals

N-([ 18 F]fluoroalkyl)-N-nitroso-4-methyl-benzensulfonamides [n-alkyl = (-CH 2 ) [ 18,19 F]F, n=2-4)] were synthesized in radiochemical yields ranging from 75-90% to provide new secondary labelling precursors for the syntheses of 18 F-labelled compounds. Preliminary decomposition studies utilizing the corresponding non-radioactive 19 F-compounds as well as the bromo containing analogous compounds were performed to evaluate their stability regarding temperature and basicity of the labelling medium. Furthermore, initial difficulties in labelling these compounds led to the development of a modified labelling procedure applying nearly solvent-free conditions. Extensive decomposition experiments…

Synthesis and preliminary in vivo evaluation of well-dispersed biomimetic nanocrystalline apatites labeled with positron emission tomographic imaging agents.

In recent years, biomimetic synthetic apatite nanoparticles (AP-NPs), having chemical similarity with the mineral phase of bone, have attracted a great interest in nanomedicine as potential drug carriers. To evaluate the therapeutic perspectives of AP-NPs through the mechanisms of action and organs they interact with, the noninvasive monitoring of their in vivo behavior is of paramount importance. To this aim, here the feasibility to radiolabel AP-NPs ("naked" and surface-modified with citrate to reduce their aggregation) with two positron emission tomographic (PET) imaging agents ([F-18]NaF and Ga-68-NO(2)AP(BP)) was investigated. [F-18]NaF was used for the direct incorporation of the radi…

Equilibrium, Kinetic and Structural Properties of Gallium(III) and Some Divalent Metal Complexes Formed with the New DATAm and DATA5m Ligands

The development of 68Ge/68Ga generators has made the positron-emitting 68Ga isotope widely accessible and raised interest in new chelate complexes of Ga3+. The hexadentate 1,4-di(acetate)-6-methyl[amino(methyl)acetate]perhydro-1,4-diazepane (DATAm) ligand and its bifunctional analogue, 1,4-di(acetate)-6-pentanoic acid[amino(methyl)acetate]perhydro-1,4-diazepane (DATA5m), rapidly form complexes with 68Ga in high radiochemical yield. The stability constants of DATAm and DATA5m complexes formed with Ga3+, Zn2+, Cu2+, Mn2+ and Ca2+ have been determined by using pH potentiometry, spectrophotometry (Cu2+) and 1H and 71Ga NMR spectroscopy (Ga3+). The stability constants of Ga(DATAm) and Ga(DATA5m)…

Decreased dopamine D2/D3-receptor binding in temporal lobe epilepsy: an [18F]fallypride PET study.

Summary: Purpose: Although animal data are suggestive, evidence for an alteration of the extrastriatal dopaminergic system in human focal epilepsy is missing. Methods: To quantify D2/D3-receptor density, we studied seven patients with temporal lobe epilepsy (TLE) and nine agematched controls with positron emission tomography (PET) by using the high-affinity dopamine D2/D3-receptor ligand [ 18 F]Fallypride ([ 18 F]FP) suitable for imaging extrastriatal binding. TLE was defined by interictal and ictal video-EEG, magnetic resonance imaging (MRI), and [ 18 F]fluorodeoxyglucose ([ 18 F]FDG)-PET and was due to hippocampal sclerosis (HS), based on histology in all patients. Primary analysis was ba…

In vivo comparison of DOTA based 68Ga-labelled bisphosphonates for bone imaging in non-tumour models.

Bone metastases are a class of cancerous metastases that result from the invasion of a tumor into bone. The solid mass which forms inside the bone is often associated with a constant dull ache and severe spikes in pain, which greatly reduce the quality of life of the patient. Numerous (99m)Tc-labeled bisphosphonate functionalised complexes are well established tracers for bone metastases imaging. The objective of this research was to evaluate the pharmacokinetics and behaviour of three DOTA based bisphosphonate functionalised ligands (BPAMD, BPAPD and BPPED), using both (68)Ga μ-PET in vivo imaging and ex vivo biodistribution studies in healthy Wistar rats. The compounds were labelled with …

Improved Efficacy of Synthesizing *MIII-Labeled DOTA Complexes in Binary Mixtures of Water and Organic Solvents. A Combined Radio- and Physicochemical Study

Typically, the synthesis of radiometal-based radiopharmaceuticals is performed in buffered aqueous solutions. We found that the presence of organic solvents like ethanol increased the radiolabeling yields of [68Ga]Ga-DOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacatic acid). In the present study, the effect of organic cosolvents [ethanol (EtOH), isopropyl alcohol, and acetonitrile] on the radiolabeling yields of the macrocyclic chelator DOTA with several trivalent radiometals (gallium-68, scandium-44, and lutetium-177) was systematically investigated. Various binary water (H2O)/organic solvent mixtures allowed the radiolabeling of DOTA at a significantly lower temperature than …

Fate of Linear and Branched Polyether-Lipids In Vivo in Comparison to Their Liposomal Formulations by 18F-Radiolabeling and Positron Emission Tomography

In this study, linear poly(ethylene glycol) (PEG) and novel linear-hyperbranched, amphiphilic polyglycerol (hbPG) polymers with cholesterol (Ch) as a lipid anchor moiety were radiolabeled with fluorine-18 via copper-catalyzed click chemistry. In vivo investigations via positron emission tomography (PET) and ex vivo biodistribution in mice were conducted. A systematic comparison to the liposomal formulations with and without the polymers with respect to their initial pharmacokinetic properties during the first hour was carried out, revealing remarkable differences. Additionally, cholesterol was directly labeled with fluorine-18 and examined likewise. Both polymers, Ch-PEG27-CH2-triazole-TEG-…

Clinical Translation and First In-Human Use of [44Sc]Sc-PSMA-617 for PET Imaging of Metastasized Castrate-Resistant Prostate Cancer

Background: Various trivalent radiometals are well suited for labeling of DOTA-conjugated variants of Glu-ureido-based prostate-specific membrane antigen (PSMA) inhibitors. The DOTA-conjugate PSMA-617 has proven high potential in PSMA radioligand therapy (PSMA-RLT) of prostate cancer as well as PET imaging when labeled with lutetium-177 and gallium-68 respectively. Considering the relatively short physical half-life of gallium-68 this positron emitter precludes prolonged acquisition periods, as required for pre-therapeutic dosimetry or intraoperative applications. In this context, the positron emitter scandium-44 is an attractive alternative for PET imaging. We report the synthesis of [44Sc…

[(11)C]PR04.MZ, a promising DAT ligand for low concentration imaging: Synthesis, efficient (11)C-O-methylation and initial small animal PET studies.

PR04.MZ was designed as a highly selective dopamine transporter inhibitor, derived from natural cocaine. Its binding profile indicates that [{sup 11}C]PR04.MZ may be suited as a PET radioligand for the non-invasive exploration of striatal and extrastriatal DAT populations. As a key feature, its structural design facilitates both, labelling with fluorine-18 at its terminally fluorinated butynyl moiety and carbon-11 at its methyl ester function. The present report concerns the efficient [{sup 11}C]MeI mediated synthesis of [{sup 11}C]PR04.MZ from an O-desmethyl precursor trifluoroacetic acid salt with Rb{sub 2}CO{sub 3} in DMF in up to 95 {+-} 5% labelling yield. A preliminary {mu}PET-experim…

Comparison Study of Two Differently Clicked 18F-Folates—Lipophilicity Plays a Key Role

Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable 18F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel 18F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the 18F-folates was investigated. 18F-Ala-folate and 18F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of …

Development and in vitro evaluation of new bifunctional 89Zr-chelators based on the 6-amino-1,4-diazepane scaffold for immuno-PET applications

Abstract Introduction Combination of hydroxamate bearing side chains with the 6-amino-1,4-diazepane scaffold provides a promising strategy for fast and stable 89Zr-labeling of antibodies. Following this approach, we hereby present the development, labeling kinetics and in vitro complex stability of three resulting bifunctional chelator derivatives both stand-alone and coupled to a model protein in comparison to different linear deferoxamine (DFO) derivatives. Methods The novel 89Zr-chelator Hy3ADA5 was prepared via amide-coupling of separately synthesized 6-amino-1,4-diazepane-6-pentanoic acid and hydroxamate-containing side chains. Two further bifunctional derivatives were synthesized by e…

Synthesis of 2-amino-6-(2-[18F]fluoro-pyridine-4-ylmethoxy)-9-(octyl-β-d-glucosyl)-purine: a novel radioligand for positron emission tomography studies of the O6-methylguanine-DNA methyltransferase (MGMT) status of tumour tissue

Abstract The synthesis of the novel glucose conjugated O6-methylguanine-DNA methyltransferase (MGMT) inhibitor 2-amino-6-(2-[18F]fluoro-pyridine-4-ylmethoxy)-9-(octyl-α- d -glucosyl)-purine is reported. This compound might serve as a radiotracer for the determination of the MGMT status of tumour tissue.

Imaging of T cell-mediated inflammation in a preclinical GvHD model using radiolabeled anti-human CD3 antibody

Gallium-68 and scandium-44 labelled radiotracers based on curcumin structure linked to bifunctional chelators: Synthesis and characterization of potential PET radiotracers

Abstract Curcumin metal complexes showed widespread applications in medicine and can be exploited as a lead structure for developing new tracers for nuclear medicine application. Herein, the synthesis, chemical characterization and radiolabelling with gallium-68 and scandium-44 of two new targeting vectors based on curcumin scaffolds and linked to the chelators 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) and 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA) are reported. Synthesis of the precursors could be achieved with a 13% and 11% yield and radiolabelling generally afforded rapid incorporation under mild conditions (>95%). Sta…

A comparative analysis of striatal and extrastriatal D2/D3 binding of five pharmacologically different “atypical” antipsychotics

PET- und SPECT-Technik: Chemie und Physik der Bildgebung

Der modernen molekularen Bildgebung unter Einsatz von radioaktiv markierten Tracersubstanzen stehen die beiden tomographischen Verfahren SPECT und PET zur Verfugung. Mit ihnen ist die nicht-invasive dreidimensionale Darstellung der raumlichen und zeitlichen Verteilung von Radiopharmaka entsprechend des physiologischen bzw. biochemischen Funktionsstatus des entsprechenden Gewebes moglich. SPECT und PET unterscheiden sich wesentlich in der Art der Strahlendetektorsysteme und den zur Anwendung geeigneten Radionukliden und Radiopharmaka. SPECT-Gerate bestehen aus ein bis drei Gamma-Kameras mit NaI-Szintillationsdetekoren, die um den liegenden Patienten rotieren. PET-Scanner werden fast ausschli…

Dependence of the mobility of tracer ions in aqueous perchlorate solutions on the hydrogen ion concentration

The dependence of the absolute individual ion mobility (AIIM) of the carrier-free radioactive ions [137Cs]Cs+, [201Tl]Tl+ and [57Co]Co2+ on the hydrogen ion concentration in aqueous perchlorate electrolyte mixtures was studied by means of the electromigration technique. The AIIM of the radioactive ions was found to decrease as the hydrogen ion concentration of the electrolyte mixture increases. Above pH > 4 there is a fairly good agreement between experimental and calculated values. Below pH 4 the experimentally observed decrease of the AIIM is not explained by the extended Debye–Huckel–Onsager limiting law. The effect can possibly be explained by a change of the dynamical properties of ele…

Improved automated synthesis of [18F]fluoroethylcholine as a radiotracer for cancer imaging.

[(18)F]Fluoroethylcholine has been recently introduced as a promising (18)F-labelled analogue of [(11)C]choline which had been previously described as a tracer for metabolic cancer imaging with positron emission tomography (PET). Due to the practical advantages of using the longer-lived radioisotope (18)F (t(1/2)=110 min), offering the opportunity of a more widespread clinical application, we established a reliable, fully automated synthesis for its production using a modified, commercially available module. [(18)F]Fluoroethylcholine was prepared from N,N-dimethylaminoethanol by iodide catalyzed alkylation with 1-[(18)F]fluoro-2-tosylethane as alkylating agent, resulting in a total radioche…

Evaluation of Safety and Dosimetry of 177Lu-DOTA-ZOL for Therapy of Bone Metastases

Palliative treatment of bone metastasis using radiolabeled bisphosphonates is a well-known concept proven to be safe and effective. A new therapeutic radiopharmaceutical for bone metastasis is 177Lu-DOTA-zoledronic acid (177Lu-DOTA-ZOL). In this study, the safety and dosimetry of a single therapeutic dose of 177Lu-DOTA-ZOL were evaluated on the basis of a series of SPECT/CT images and blood samples. Methods: Nine patients with exclusive bone metastases from metastatic castration-resistant prostate cancer (mCRPC) (70.8 ± 8.4 y) and progression under conventional therapies participated in this prospective study. After receiving 5,780 ± 329 MBq 177Lu-DOTA-ZOL, patients underwent 3-dimensional …

Impact of prompt gamma emission of 44Sc on quantification in preclinical and clinical PET systems

Abstract 44Sc is an increasingly investigated positron emitter for use in positron emission tomography (PET) imaging. However, 44Sc is a non-pure positron emitter, since prompt photons are co-emitted during the decay process. This study investigates coincidence energy spectra of 44Sc and its impact on PET quantification on a preclinical and clinical PET system in comparison with 18F. The raw data of the coincidence events revealed characteristic differences comparing the photon energy distribution of 44Sc and 18F. Due to prompt gamma emission of 44Sc, activity recovery is underestimated on PET systems. However, clinical PET imaging of 44Sc with acceptable quantitative accuracy appears feasi…

UTSW Small Animal Positron Emission Imager

A Small Animal Imager (SAI) for PET has been designed, built, tested in phantoms, and applied to investigations in mice and rats. The device uses principles based on gamma-ray induced scintillation in crossed fiber optic detectors connected to Position Sensitive Photomultiplier Tubes (PSPMT). Each detector consists of an epoxied stack of 28 layers of 135 round 1 mm BCF-10 scintillating plastic fibers. The overlap region forms a 13.5times13.5times2.8 cm3 detector volume. Scintillating light from the fibers is detected by two (X and Y directions) Hamamatsu R-2486 PSPMTs with 16 anode wires in each of two orthogonal directions. A centroid-finding algorithm gives the position of a light cluster…

Radiolabelling and preliminary evaluation of 68Ga-tetrapyrrole derivatives as potential tracers for PET

article i nfo Tetrapyrroles are multisided natural products which are of relevance in clinical medicine. Owing to their specific accumulation in tumour tissue, porphyrins, metalloporphyrins and chlorins have been used as in photodynamic therapy and optical imaging. Moreover, their specific uptake into inflammatory atheromatous plaques via LDL endocytosis has been reported. The present study is concerned with the synthesis of 68 Ga labelled porphyrin derivatives and an in vitro assessment of the utility of radiotracers in positron emission tomography. A set of five porphyrin derivatives were labelled using 68 Ga from a commercially obtained radionuclide generator. Dedicated post-processing o…

The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia.

Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D2/D3 receptor occupancy was statistically significantly higher in cortical (inferior tem…

[18F]PR04.MZ PET/CT Imaging for Evaluation of Nigrostriatal Neuron Integrity in Patients With Parkinson Disease.

Introduction Degeneration of dopaminergic, nigrostriatal neurons is the hallmark of Parkinson disease (PD), and PET quantification of dopamine transporters is a widely accepted method for differential diagnosis between idiopathic PD and essential tremor. [18F]PR04.MZ is a new PET tracer with excellent imaging properties allowing for precise quantification of striatal and extrastriatal dopamine transporter. Here we describe our initial experience with [18F]PR04.MZ PET/CT in a larger cohort of healthy controls and PD patients as a proof-of-concept study for this tracer. Methods Eighteen healthy subjects, 19 early PD patients (Hoehn-Yahr I–II), and 13 moderate-advanced PD patients (Hoehn-Yahr …

Dopamine D2/3 receptor occupancy by quetiapine in striatal and extrastriatal areas

Quetiapine is next to clozapine an antipsychotic agent that exerts hardly any extrapyramidal side-effects at clinical efficacious doses. Some previous receptor occupancy studies reported preferential extrastriatal D2/3 receptor (D2/3R)-binding properties of second-generation antipsychotics and suggested this as possible reason for improved tolerability. This positron emission tomography (PET) investigation was designed to compare the occupancy of dopamine D2/3Rs by quetiapine in striatal and extrastriatal brain regions. Therefore, a cohort of 16 quetiapine-treated psychotic patients underwent an [18F]fallypride (FP) PET scan. Due to the high affinity of FP and its comparatively long half-li…

A convenient chemo-enzymatic synthesis and 18F-labelling of both enantiomers of trans-1-toluenesulfonyloxymethyl-2-fluoromethyl-cyclopropane

The present report is concerned with a stereoselective, reliable route to trans-1,2-disubstituted cyclopropanes and in particular to (S,S)-1-tosyloxymethyl-2-fluoromethyl-cyclopropane (1) and (R,R)-1-tosyloxymethyl-2-fluoromethyl-cyclopropane (ent-1) as conformationally restricted, terminally fluorinated C4-building blocks for medicinal chemistry. The enzymatic kinetic resolution based synthesis of 1 and ent-1 utilises inexpensive, commercially available starting materials. It is based on enantiomeric resolution of rac-cyclopropane carboxylic esters using esterase from Streptomyces diastatochromogenes. Both enantiomers of 1 were prepared selectively in high overall yield over nine steps, st…

From Bench to Bedside—The Bad Berka Experience With First-in-Human Studies

Precision oncology is being driven by rapid advances in novel diagnostics and therapeutic interventions, with treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations. Inherent in the theranostics paradigm is the assumption that diagnostic test results can precisely determine whether an individual is likely to benefit from a specific treatment. As part and integral in the current era of precision oncology, theranostics in the context of nuclear medicine aims to identify the appropriate molecular targets in neoplasms (diagnost…

AAZTA5-BN as a Versatile Probe for Radiometal Labelling, Nuclear Imaging and Radionuclide Therapy of Gastrin Releasing Peptide Positive Tumors

The Szilard–Chalmers effect in macrocyclic ligands to increase the specific activity of reactor-produced radiolanthanides: Experiments and explanations

Abstract Successful utilization of medical isotopes in the radiolabeling reactions to a significant degree depends on the technically achievable specific activity. In this respect, the Szilard-Chalmers effect is considered in detail as a radiochemical tool to increase the specific activity of radionuclides produced by direct nuclear reactions. In the present study, a physico-chemical model is described utilizing the specific aspects of thermodynamically and kinetically stabilised metal-ligand complexes. The approach is applied as a proofof- principle study to increase the specific activity of 166Ho, produced via the (n, γ) nuclear reaction. As a target material, 165Ho-DOTA is used. In this …

68 Ga‐Labelled Tropane Analogues for the Visualization of the Dopaminergic System

Abstract The development of radiometal‐labelled pharmaceuticals for neuroimaging could offer great potential due to easier handling during labelling and availability through radionuclide generator systems. Nonetheless, to date, no such tracers are available for positron emission tomography, primarily owing to the challenge of crossing the blood–brain barrier (BBB) and loss of affinity through chelator attachment. We have prepared a variety of 68Ga‐labelled phenyltropanes showing that, through a simple hydrocarbon‐linker, it is possible to introduce a chelator onto the lead structure while maintaining its high affinity for hDAT (human dopamine transporter) and simultaneously achieving adequa…

Inhibition of O6-Methylguanine-DNA Methyltransferase by Glucose-Conjugated Inhibitors: Comparison with Nonconjugated Inhibitors and Effect on Fotemustine and Temozolomide-Induced Cell Death

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is an important suicide enzyme involved in the defense against O(6)-alkylating mutagens. It also plays a role in the resistance of tumors to anticancer drugs targeting the O(6)-position of guanine, such as temozolomide and fotemustine. Several potent MGMT inhibitors have been developed sensitizing cells to O(6)-alkylating agents. Aimed at targeting MGMT inhibitors to tumor cells, we synthesized MGMT inhibitory compounds conjugated with glucose to improve uptake in tumor cells. Here, we compared O(6)-benzylguanine, O(6)-2-fluoropyridinylmethylguanine (O(6)FPG), O(6)-3-iodobenzylguanine, O(6)-4-bromothenylguanine, and O(6)…

Radioactive labeling of defined HPMA-based polymeric structures using [18F]FETos for in vivo imaging by positron emission tomography.

During the last decades polymer-based nanomedicine has turned out to be a promising tool in modern pharmaceutics. The following article describes the synthesis of well-defined random and block copolymers by RAFT polymerization with potential medical application. The polymers have been labeled with the positron-emitting nuclide fluorine-18. The polymeric structures are based on the biocompatible N-(2-hydroxypropyl)-methacrylamide (HPMA). To achieve these structures, functional reactive ester polymers with a molecular weight within the range of 25,000-110,000 g/mol were aminolyzed by 2-hydroxypropylamine and tyramine (3%) to form (18)F-labelable HPMA-polymer precursors. The labeling procedure…

Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging.

Background In this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal-labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA-linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177. Results Short linkers and as low as 1.6% DOTA were enough to obtain labeling yields > 90%. Alkoxy linkers generally exhibited lower labeling yields than alkane analogues despite of similar chain length and DOTA incorporation rate. High sta…

The Basics of Nuclear Chemistry and Radiochemistry: An Introduction to Nuclear Transformations and Radioactive Emissions

Radiopharmaceutical chemistry and nuclear medicine make use of radioactive elements and compounds labeled with them. This chapter describes the fundamentals of radioactivity in the context of life sciences. It addresses principal questions such as: What is the composition of an atomic nucleus and what are the forces which hold nucleons bound within the nucleus? Even so, some nuclei are stable, and many others are not—why? The fate of unstable nuclei is transforming into more stable nucleon configurations—but what are the basic pathways to do so? What’s going on inside the nucleus? What are the energetics and velocities of these transformations? And finally, the various changes inside the nu…

Targeting of immune cells with trimannosylated liposomes

Processing of Generator-Produced 68Ga for Medical Application

The (68)Ge/(68)Ga generator provides an excellent source of positron-emitting (68)Ga. However, newly available "ionic" (68)Ge/(68)Ga radionuclide generators are not necessarily optimized for the synthesis of (68)Ga-labeled radiopharmaceuticals. The eluates have rather large volumes, a high concentration of H(+) (pH of 1), a breakthrough of (68)Ge, increasing with time or frequency of use, and impurities such as stable Zn(II) generated by the decay of (68)Ga, Ti(IV) as a constituent of the column material, and Fe(III) as a general impurity.We have developed an efficient route for the processing of generator-derived (68)Ga eluates, including the labeling and purification of biomolecules. Prec…

Dimethylpyridin-4-ylamine-Catalysed Alcoholysis of 2-Amino-N,N,N-Trimethyl-9H-purine-6-ylammonium Chloride: An Effective Route to O6-Substituted Guanine Derivatives from Alcohols with Poor Nucleophilicity

Dimethylpyridin-4-ylamine (DMAP)-catalysed reactions of 2-amino-N,N,N-trimethyl-9H-purine-6-ylammonium chloride with fluoropyridine methoxides and various other alkoxides in DMSO at 60 °C gave the corresponding coupling products in moderate to good yields between 20-87%. Under these reaction conditions, fluorinated O 6 -substituted Guanine derivatives have been synthesized which could not be obtained via known analogous literature procedures. The respective yields of known O 6 -substituted guanine derivatives could be significantly improved by using this method. The efficient use of DMAP as an excellent nucleophilic catalyst in the syntheses of O 6 -substituted Guanine derivatives has thus …

Synthesis and first evaluation of new 18F-labelled sulfonylureas for the determination of the beta-cell status in vivo

The syntheses and first in vitro evaluations for two fluoride bearing sulfonylurea derivatives are reported. Firstly, the tolbutamide derivative 1-[4-(2-[18F]fluoroethoxy)benzenesulfonyl]-3-butyl urea (2-[18F]fluoroethyl-tolbutamide) could be labeled efficiently with [18F]fluoride. Subsequently, the glibenclamid derivative N-(2-(4-(N-((cyclohexylamino)carbonyl)sulfonylamino)phenyl)ethyl) 2-(5-chloro-2-[18F]fluorethoxy)phenyl) formamide (2-[18F]fluoroethyl-glibenclamide) was labeled with [18F]fluoride in high yields. Its ability to induce insuline secretion from rat beta-cells in relation to the original glibenclamide was determined.

72/74As-labeling of HPMA based polymers for long-term in vivo PET imaging

Abstract In the context of molecular imaging, various polymers based on the clinically approved N-(2-hydroxypropyl)-methacrylamide (HPMA) have been radio-labeled using longer-living positron emitters 72As t1/2 = 26 h or 74As t1/2 = 17.8 d. This approach may lead to non-invasive determination of the long-term in vivo fate of polymers by PET (positron emission tomography). Presumably, the radio label itself will not strongly influence the polymer structure due to the fact that the used nuclide binds to already existing thiol moieties within the polymer structure. Thus, the use of additional charges or bulky groups can be avoided.

NMR Hyperpolarization of Established PET Tracers

Development of FAP-inhibitors based on squaric acid linked DOTA and DATA5m chelators

Dopamine, Noradrenaline and Serotonin Receptor Densities in the Striatum of Hemiparkinsonian Rats following Botulinum Neurotoxin-A Injection.

Abstract Parkinson’s disease (PD) is characterized by a degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) that causes a dopamine (DA) deficit in the caudate-putamen (CPu) accompanied by compensatory changes in other neurotransmitter systems. These changes result in severe motor and non-motor symptoms. To disclose the role of various receptor binding sites for DA, noradrenaline, and serotonin in the hemiparkinsonian (hemi-PD) rat model induced by unilateral 6-hydroxydopamine (6-OHDA) injection, the densities of D1, D2/D3, α1, α2, and 5HT2A receptors were longitudinally visualized and measured in the CPu of hemi-PD rats by quantitative in vitro receptor autorad…

Radiosynthesis of (±)-(2-((4-(2-[18F]fluoro-ethoxy)phenyl)bis(4-methoxy-phenyl)methoxy)ethylpiperidine-3-carboxylic acid: a potential GAT-3 PET ligand to study GABAergic neuro-transmissionin vivo

A dysfunction of GABAergic neurotransmission is related to diseases such as epilepsy, Huntington-disease and Parkinson-syndrome. A new 18F-fluorine labelled GABA transporter ligand for the GABA-transporter subtype GAT-3 was developed which may allow the in vivo visualisation of GABAergic neurotransmission. The precursors ethyl (2-(4-hydroxyphenyl)bis(4-methoxyphenyl)-methoxy)ethyl)-piperidine-3-carboxylate and ethyl(2-((4-(2-tosylethoxy)phenyl)-bis(4-methoxyphenyl)-methoxy) ethyl)-piperidine3-carboxylate were synthesised and labelled by the use of 2-[18F]fluoroethyltosylate or [18F]fluoride. Subsequent cleavage of the ester moiety gave the final product (±)-(2-((4-(2-[18F]fluoroethoxy)pheny…

Scandium(III) complexes of monophosphorus acid DOTA analogues: a thermodynamic and radiolabelling study with 44 Sc from cyclotron and from a 44 Ti/ 44 Sc generator †

International audience; The complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylene-phosphinic (DO3AP PrA and DO3AP ABn) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(III) complexes were determined by potentiometry combined with 45 Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc–DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(III) precludes stability constant determination of the Sc–DO3AP complex. These results we…

Measurement of Protein Synthesis: In Vitro Comparison of 68Ga-DOTA-Puromycin, [3H]Tyrosine, and 2-Fluoro-[3H]tyrosine

Aim: Puromycin has played an important role in our understanding of the eukaryotic ribosome and protein synthesis. It has been known for more than 40 years that this antibiotic is a universal protein synthesis inhibitor that acts as a structural analog of an aminoacyl-transfer RNA (aa-tRNA) in eukaryotic ribosomes. Due to the role of enzymes and their synthesis in situations of need (DNA damage, e.g., after chemo- or radiation therapy), determination of protein synthesis is important for control of antitumor therapy, to enhance long-term survival of tumor patients, and to minimize side-effects of therapy. Multiple attempts to reach this goal have been made through the last decades, mostly u…

Synthesis, Labeling and Preclinical Evaluation of a Squaric Acid Containing PSMA Inhibitor Labeled with 68 Ga: A Comparison with PSMA‐11 and PSMA‐617

The L-lysine urea-L-glutamate (KuE) represents a key motif in recent diagnostic and therapeutic radiopharmaceuticals targeting the prostate specific membrane antigen (PSMA). Using a squaric acid moiety for coupling of KuE with a radioactive label, the squaric acid as a linker in the PSMA ligand seems to mimic the aromatic structure of the naphthylalanine unit on PSMA-617. In this work, we investigate the influence of squaric acid moiety on the biological activity of the compound carrying a KuE motif and three typical chelates. The derivatives TRAM.SA.KuE, DOTAGA.SA.KuE and NODAGA.SA.KuE were all synthesized in straightforward organic reactions and purified by HPLC afterward. Different amoun…

Opiate-induced dopamine release is modulated by severity of alcohol dependence: an [(18)F]fallypride positron emission tomography study.

Background Preclinical data implicate the reinforcing effects of alcohol to be mediated by interaction between the opioid and dopamine systems of the brain. Specifically, alcohol-induced release of β-endorphins stimulates μ-opioid receptors (MORs), which is believed to cause dopamine release in the brain reward system. Individual differences in opioid or dopamine neurotransmission have been suggested to be responsible for enhanced liability to abuse alcohol. In the present study, a single dose of the MOR agonist remifentanil was administered in detoxified alcohol-dependent patients and healthy control subjects to mimic the β-endorphin-releasing properties of ethanol and to assess the effect…

Modifying the body distribution of HPMA-based copolymers by molecular weight and aggregate formation.

There is a recognized need to create well-defined polymer probes for in vivo and clinical positron emission tomography (PET) imaging to guide the development of new generation polymer therapeutics. Using the RAFT polymerization technique in combination with the reactive ester approach, here we have synthesized well-defined and narrowly distributed N-(2-hydroxypropyl)methacrylamide homopolymers (pHPMA) (P1* and P2*) and random HPMA copolymers consisting of hydrophilic HPMA and hydrophobic lauryl methacrylate comonomers (P3* and P4*). The polymers had molecular weights below (P1* and P3*) and above the renal threshold (P2* and P4*). Whereas the homopolymers dissolve in isotonic solution as in…

Synthesis, labelling and evaluation of hydantoin-substituted indole carboxylic acids as potential ligands for positron emission tomography imaging of the glycine binding site of the N-methyl-d-aspartate receptor

The N-methyl- d-aspartate (NMDA) receptor as a type of ionotropic glutamatergic receptors is essential for physiological processes such as learning, memory and synaptic plasticity. A glutamate-induced overactivation of these receptors, accompanied by increased intracellular calcium concentration, causes cell injury and leads to a large number of acute or chronic neurological disorders, such as stroke, trauma, Parkinson's disease and Alzheimer's disease. In an attempt to visualise the glutamatergic neurotransmission in vivo with positron emission tomography, novel fluoroethoxy- and methoxy-substituted reference compounds based on the lead structure of a hydantoin-substituted indole-2-carboxy…

High opiate receptor binding potential in the human lateral pain system

To determine how opiate receptor distribution is co-localized with the distribution of nociceptive areas in the human brain, eleven male healthy volunteers underwent one PET scan with the subtype-nonselective opioidergic radioligand [(18)F]fluoroethyl-diprenorphine under resting conditions. The binding potential (BP), a parameter for the regional cerebral opioid receptor availability, was computed using the occipital cortex as reference region. The following regions of interest (ROIs) were defined on individual MR images: thalamus, sensory motor strip (SI/MI area), frontal operculum, parietal operculum, anterior insular cortex, posterior insular cortex, anterior cingulate cortex (ACC; peri-…

Optimization of Labeling PSMAHBED with Ethanol-Postprocessed 68Ga and Its Quality Control Systems

Radiolabeling of the prostate-specific membrane antigen (PSMA) inhibitor Glu-NH-CO-NH-Lys(Ahx) using the 68Ga chelator HBED-CC (PSMAHBED) allows imaging of prostate cancer lesions because of high expression of PSMA in prostate carcinoma cells and in bone metastases and lymph nodes related to the disease. The aim of this work was to optimize labeling of 68Ga-PSMAHBED using the efficient cation-exchange postprocessing of 68Ga as well as the development of a thin-layer chromatography (TLC)-based quality control system. Methods: Labeling was optimized for online ethanol-postprocessed 68Ga eluate investigating various parameters, such as buffer molarity (0.1-1 M), temperature (25°C-90°C), tracer…

Generator-Based Radiopharmaceuticals for PET Dosimetry Before, During, and After Endoradiotherapy

Generator-derived radionuclides for PET/CT imaging are promising for optimizing targeted radiotherapy by an individual patient-based approach, applying pre-therapeutic evaluation, dosimetric calculations, and for measuring treatment response after radionuclide therapy. To realize this vision, sophisticated nuclear chemistry and radiopharmaceutical chemistry should coincide with quantitative molecular imaging and dosimetric calculations.

Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach

(1) Background: Prostate-specific membrane antigen (PSMA) has been extensively studied in the last decade. It became a promising biological target in the diagnosis and therapy of PSMA-expressing cancer diseases. Although there are several radiolabeled PSMA inhibitors available, the search for new compounds with improved pharmacokinetic properties and simplified synthesis is still ongoing. In this study, we developed PSMA ligands with two different hybrid chelators and a modified linker. Both compounds have displayed a promising pharmacokinetic profile. (2) Methods: DATA5m.SA.KuE and AAZTA5.SA.KuE were synthesized. DATA5m.SA.KuE was labeled with gallium-68 and radiochemical yields of various…

Vulnerability to psychotogenic effects of ketamine is associated with elevated D2/3-receptor availability.

Previous positron emission tomography (PET) studies employing competition paradigms have shown either no change or substantial declines in striatal ( 11 C)-raclopride binding after challenge with psychotogenic doses of the N-methyl-D-aspartate antagonist ketamine. We sought to probe the relationship between the severity of ketamine-induced psychotic symptoms and altered dopamine D2/3 receptor availability throughout brain using the high affinity ligand ( 18 F)-fallypride (FP). PET recordings were obtained in a group of 10 healthy, young male volunteers, in a placebo condition, and in the course of an infusion with ketamine at a psychotomimetic dose. Administration of the Positive and Negati…

Synthesis and in vitro evaluation of galanthamine derivatives for examination of nicotinic acetylcholine receptor system

ISunmrary: The syntheses and radioactive labeling of several galanthamine derivatives, 6-O-demethyl-6-O-fluoroethylgalanthamine, 10-N-demethyl-lO-Nfluoroethylgalanthamine and N-methylgalanthaminium are reported. First ill vitro evaluations were carried out to determine their properties as allosterically potentiating ligands of nicotinic receptors. N-methylgalanthaminium was found to be a promising candidate for further investigations. The most commonly applied therapeutic approach to balance nicotinic cholinergic deficits in Alzheimer’s disease (AD) patients is the administration of acetylcholinesterase inhibitors (AChE-I) although they have been proven to be of limited therapeutic value [ …

Complex formation of Tb3+ with glycolate, D-gluconate and α-isosaccharinate in neutral aqueous perchlorate solutions

Summary An electromigration technique was used for measurements of metal-ligand formation constants of non-carrier-free 160Tb3+ with glycolate, D-gluconate and α-isosaccharinate ligands. The overall ion mobilities of Tb at different concentrations of the ligands were measured in chemically inert perchlorate solutions (pH 7 and T= 298.1K) with an overall ionic strength μ = 0.1. The stepwise stoichiometric stability constants are: Tb3+/glycolate: log K 1=2.72(18), log K 2=1.73(19), log K 3= 1.12(17), Tb3+/D-gluconate: log K 1=2.96(11), log K 2=2.60(11), log K 3=1.13(9), Tb3+/α-ISA: log K 1=3.07(8), log K 2 = 2.69(11), log K 3 = 1.80(12).

Production and Radiochemical Separation of the Auger Electron Emitter140Nd

Among the Auger electron emitters, the radiolanthanide 140Nd has some unique nuclear properties with potential for endoradiotherapeutic applications. In the present study, 140Nd was produced via the 140Ce(3He,3n) nuclear process at the FZ Julich CV28 cyclotron, irradiating CeO2 with 3He particles of 36 MeV primary energy. Yields of about 5 MBq 140Nd per microAh were experimentally obtained. Batch yields of > 100 MBq 140Nd were reached. 140Nd was separated in 75 +/- 5% radiochemical yield using a two-step process, first by extracting the bulk of the target material according to a Ce(IV)/Nd(III) separation, then by final ion exchange purification.

Striatal and extrastriatal D2/D3-receptor-binding properties of ziprasidone: a positron emission tomography study with [18F]Fallypride and [11C]raclopride (D2/D3-receptor occupancy of ziprasidone).

To elucidate the Batypicality( of ziprasidone, its striatal and extrastriatal D2/D3-receptor binding was characterized in patients with schizophrenia under steady-state conditions. These data were compared with striatal receptor occupancy values after single-dose ziprasidone ingestion in healthy controls. ( 18 F)fallypride positron emission tomography (PET) recordings were obtained in 15 patients under steady-state ziprasidone treatment at varying time points after the last dose. Binding potentials were calculated for striatal and extrastriatal regions. D2/D3-receptor occupancies were expressed relative to binding potentials in 8 unmedicated patients. In a parallel ( 11 C)raclopride-PET stu…

The applicability of SRTM in [18F]fallypride PET investigations: Impact of scan durations

The high-affinity radioligand [18F]fallypride (FP) is frequently used for quantification of striatal/extrastriatal D2/3 receptors and the receptor occupancies of antipsychotics (APs). Its 110 minutes half-life allows long scan durations. However, the optimum scan duration is a matter of debate. This investigation focuses on scan-duration-related effects on simplified reference tissue model (SRTM) results and the time point of transient equilibrium in a large sample of dynamic FP positron emission tomography (PET) scans. Fifty drug-free and 50 AP-treated subjects underwent FP-PET scans (180 minutes scan duration). The binding potential ( BPND) of the putamen, thalamus, and temporal cortex w…

Research Letter: Structural Combination of Established 5-HT2A Receptor Ligands: New Aspects of the Binding Mode

MH.MZ, MDL 100907, and altanserin are structurally similar 4-benzoyl-piperidine derivatives and are well accommodated to receptor interaction models. We combined structural elements of different high-affinity and selective 5-HT(2A) antagonists, as MH.MZ, altanserin, and SR 46349B, to improve the binding properties of new compounds. Three new derivatives were synthesized with a 4-benzoyl-piperidine moiety as the lead structure. The in vitro affinity of the novel compounds was determined by a [³H]MDL 100907 competition binding assay. The combination of MH.MZ and SR 46349B resulted in a compound (8) with a moderate affinity toward the 5-HT(2A) receptor (K(i) = 57 nm). The remarkably reduced af…

Clinical evaluation of [68Ga]Ga-DATA-TOC in comparison to [68Ga]Ga-DOTA-TOC in patients with neuroendocrine tumours

Abstract Introduction [68Ga]Ga-DATA-TOC is a new radiolabelled somatostatin-analogue for positron emission tomography (PET) imaging of neuroendocrine tumours. Its advantage over DOTA-conjugated compounds is the possibility for high-efficiency labelling with gallium-68 quickly at room temperature with high reliability and without the need for product purification, which enables the development of an instant kit-type labelling method. We evaluated its imaging characteristics in patients with neuroendocrine tumours in comparison to [68Ga]Ga-DOTA-TOC. Methods 19 patients imaged with [68Ga]Ga-DATA-TOC were retrospectively analysed and uptake in normal tissues was compared with a group of 19 pati…

[ 18 F]Fluoroethylflumazenil: a novel tracer for PET imaging of human benzodiazepine receptors

5-(2'-[18F]Fluoroethyl)flumazenil ([18F]FEF) is a fluorine-18 labelled positron emission tomography (PET) tracer for central benzodiazepine receptors. Compared with the established [11C]flumazenil, it has the advantage of the longer half-life of the fluorine-18 label. After optimisation of its synthesis and determination of its in vitro receptor affinities, we performed first PET studies in humans. PET studies in seven healthy human volunteers were performed on a Siemens ECAT EXACT whole-body scanner after injection of 100-280 MBq [L8F]FEF. In two subjects, a second PET scan was conducted after pretreatment with unlabelled flumazenil (1 mg or 2.5 mg i.v., 3 min before tracer injection). A t…

Application of tris-allyl-DOTA in the preparation of DOTA–peptide conjugates

Abstract The synthesis of tris-allyl-DOTA starting from cyclen and its application in the preparation of DOTA–peptide conjugates is reported. Clinically important conjugates such as DOTA–Tyr3-octreotide (DOTA–TOC), DOTA–Tyr3-octreotate (DOTA–TATE) as well as a DOTA–RGD peptide were synthesized in high yields with Fmoc solid phase peptide synthesis. The final, extremely reliable de-allylation was achieved on solid phase by different methods identifying morpholine/Pd(0) as the most suitable one obtaining all DOTA peptide conjugates in high yields. All DOTA–peptides were purified by reversed phase HPLC and structural identity was proved using MALDI-TOF mass spectrometry.

A DOTA based bisphosphonate with an albumin binding moiety for delayed body clearance for bone targeting

Radiolabeled bisphosphonates are commonly used in the diagnosis and therapy of bone metastases. Blood clearance of bisphosphonates is usually fast and only 30%-50% of the injected activity is retained in the skeleton, while most of the activity is excreted by the urinary tract. A longer blood circulation may enhance accumulation of bisphosphonate compounds in bone metastases. Therefore, a chemically modified macrocyclic bisphosphonate derivative with an additional human albumin binding entity was synthesized and pharmacokinetics of its complex was evaluated. The DOTA-bisphosphonate conjugate BPAMD was compared against the novel DOTAGA-derived albumin-binding bisphosphonate DOTAGA(428-d-Lys)…

Synthesis of a Tyr3-octreotate conjugated closo-carborane [HC2B10H10]: a potential compound for boron neutron capture therapy

Abstract A novel Tyr 3 -octreotate conjugated closo -carborane as a potential compound for boron neutron capture therapy was obtained via Fmoc solid phase peptide synthesis. The boron cluster [C 2 B 10 H 11 ] was introduced through the reaction of 6,9-bis(acetonitrile)decaborane and 5-hexynoic acid yielding a new closo -carborane conjugated carboxylic acid which was coupled subsequently with solid phase conjugated Tyr 3 -octreotate. The final boron-containing peptide was purified by preparative reverse phase HPLC and structural identity was proved applying MALDI-TOF mass spectrometry.

Separation and purification of no-carrier-added arsenic from bulk amounts of germanium for use in radiopharmaceutical labelling

AbstractRadioarsenic labelled radiopharmaceuticals could add special features to molecular imaging with positron emission tomography (PET). For example the long physical half-lives of72As (T1/2=26 h) and74As (T1/2=17.8 d) in conjunction with their high positron branching rates of 88% and 29%, respectively, allow the investigation of slow physiological or metabolical processes, like the enrichment and biodistribution of monoclonal antibodies in tumour tissue or the characterization of stem cell trafficking. A method for separation and purification of no-carrier-added (nca) arsenic from irradiated metallic germanium targets based on distillation and anion exchange is developed. It finally con…

Direct radiofluorination of [18F]MH.MZ for 5-HT2A receptor molecular imaging with PET

Imaging the serotonin 2A neuroreceptor with positron emission tomography has been carried out with [11C]MDL 100907 and [18F]altanserin for years. Recently, the MDL 100907 analogue [18F]MH.MZ was developed by combining the increased selectivity profile of MDL 100907 and the favourable radiophysical properties of fluorine-18. Here, we want to report the synthesis of [18F]MH.MZ via direct radiofluorination. Unfortunately, the direct radiofluorination did not have any significant benefits over the indirect labelling method. This is mainly because the precursor for the direct labelling approach is not completely stable and slowly decomposes. However, only one HPLC separation is necessary for the…

68Ge/68Ga Generators: Past, Present, and Future

In 1964, first (68)Ge/(68)Ga radionuclide generators were described. Although the generator design was by far not adequate to our today's level of chemical, radiopharmaceutical and medical expectations, it perfectly met the needs of molecular imaging of this period. (68)Ga-EDTA as directly eluted from the generators entered the field of functional diagnosis, in particular for brain imaging. A new type of generators became commercially available in the first years of the 21st century. Generator eluates based on hydrochloric acid provided "cationic" (68)Ga instead of "inert" (68)Ga-complexes and opened new pathways of Me(III) based radiopharmaceutical chemistry. The impressive success of util…

Synthesis of tritium labeled (�)-1-[2(triphenylmethoxy)ethyl]-3-piperidinecarboxylic acid: a possible compound to determine the efficacy of potential GABA transporter substancesin vitro

(±)-1-[2-(Triphenyl[ 3 H]methoxy)ethyl]-3-piperidinecarboxylic acid ([ 3 H]SNAP-5114) with a specific activity of 40 Ci/mmol was prepared in a two step synthesis starting from ethyl (2-(4-hydroxyphenyl)bis(4-methoxyphenyl)methoxy)-ethyl)piperidine-3-carboxylate and [ 3 H]methyliodide with subsequent hydrolysis of the resulting ester with lithium hydroxide to yield the desired [ 3 H]SNAP-5114.

Synthesis and preliminary evaluation of (R,R)(S,S) 5-(2-(2-[4-(2-[18F]fluoroethoxy)phenyl]-1-methylethylamino)-1-hydroxyethyl)-benzene-1,3-diol ([18F]FEFE) for the in vivo visualisation and quantification of the β2-adrenergic receptor status in lung

The 18 F-labeled b2-adrenergic receptor ligand (R,R)(S,S) 5-(2-(2-(4-(2-( 18 F)fluoroethoxy)phenyl)-1-methylethylamino)-1- hydroxyethyl)-benzene-1,3-diol, a derivative of the original highly selective racemic fenoterol, was synthesized in an overall radio- chemical yield of 20% after 65 min with a radiochemical purity higher than 98%. The specific activity was in the range of 50-60 GBq/mmol. In vitro testing of the non-radioactive fluorinated fenoterol derivative with isolated guinea pig trachea was conducted to obtain an IC50 value of 60 nM. Preliminary ex vivo organ distribution and in vivo experiments with positron emission tomography (PET) on guinea pigs were performed to study the biod…

Automated synthesis and purification of [18F]fluoro-[di-deutero]methyl tosylate

Automated synthetic procedures of [ 18 F]fluoro-[di-deutero]methyl tosylate on a GE TRACERlab FX F-N module and a non-commercial synthesis module have been developed. The syntheses included azeotropic drying of the [ 18 F]fluoride, nucleophilic 18 F-fluorination of bis(tosyloxy)-[di-deutero]methane, HPLC purification and subsequent formulation of the synthesized [ 18 F]fluoro-[di-deutero]methyl tosylate (d2-[ 18 F]FMT) in organic solvents. Automation shortened the total synthesis time to 50min, resulting in an average radiochemical yield of about 50% and high radiochemical purity (>98%). The possible application of this procedure to commercially available synthesis modules might be of signi…

Vascular imaging of solid tumors in rats with a radioactive arsenic-labeled antibody that binds exposed phosphatidylserine.

Abstract Purpose: We recently reported that anionic phospholipids, principally phosphatidylserine, become exposed on the external surface of vascular endothelial cells in tumors, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we tested the hypothesis that a chimeric monoclonal antibody that binds phosphatidylserine could be labeled with radioactive arsenic isotopes and used for molecular imaging of solid tumors in rats. Experimental Design: Bavituximab was labeled with 74As (β+, T1/2 17.8 days) or 77As (β−, T1/2 1.6 days) using a novel procedure. The radionuclides of arsenic were selected because their long half-lives are consistent w…

Asymmetry in dopamine D2/3 receptors of caudate nucleus is lost with age

Molecular and functional imaging techniques reveal evidence for lateralization of human cerebral function. Based on animal data, we hypothesized that asymmetry in dopamine neurotransmission declines during normal aging. In order to test this hypothesis, we measured dopamine D2/3 receptor availability with [18F]desmethoxyfallypride-PET (DMFP) in putamen and caudate nucleus (NC) of 21 healthy, right-handed males (24-60 years; 35+/-10). For volumetric analysis, high-resolution T1-weighted MR-images were obtained in 18 of the PET-subjects in order to assess possible age-related decreases in NC and putamen volume. The calculated DMFP binding potentials (BP) showed a right-ward asymmetry in NC of…

Radiosynthesis of 1-(4-(2-[18F]fluoroethoxy)benzenesulfonyl)-3-butyl urea: a potentialβ-cell imaging agent

Summary Tolbutamide (1) is a sulfonurea agent used to stimulate insulin secretion in type 2 diabetic patients. Its analogue 1-(4-(2-[ 18 F]fluoroethoxy)benzenesulfonyl)-3butyl urea (3) was synthesized in overall radiochemical yields of 45% as a potential b-cell imaging agent. Compound 3 was synthesized by 18 F-fluoroalkylation of the corresponding hydroxy precursor (2 )w ith 2-[ 18 F]fluoroethyltosylate in DMF at 1208C for 10 min followed by purification with HPLC in a synthesis time of 50 min. Insulin secretion experiments of the authentic 19 F-standard compound on rat islets showed that the compound has a similar stimulating effect on insulin secretion as that of tolbutamide (1). The part…

Post-elution processing of 44Ti/44Sc generator-derived 44Sc for clinical application

The (44)Ti/(44)Sc (T(1/2)(44)Ti=60a) generator provides cyclotron-independent access to positron-emitting (44)Sc (T(1/2)=3.97d) for PET imaging. This work aims to post-elution processing of initial (44)Sc generator eluates in order to reduce its volume, HCl concentration and remove the oxalate anions. The on-line adsorption of (44)Sc on cationic resin AG 50W-X8 (200-400 mesh, H(+)-form) is achieved with >98% efficacy. Subsequently, the purified (44)Sc is desorbed by using 3ml of 0.25M ammonium acetate (pH=4.0). The post-processing takes 10min. The overall yield of the post-processing reached 90%, which is referred to the (44)Sc obtained from the (44)Ti/(44)Sc generator. In addition to the c…

The Use of the Macrocyclic Chelator DOTA in Radiochemical Separations

AAZTA5.SA.KuE, a versatile tool for theranostic application – labeling, in vitro, and first in vivo-investigation of [ 177 Lu]Lu- AAZTA 5 .SA.KuE

Development of a γ-γ-perturbed angular correlation one-detector method (1-PAC) for investigation of physico-chemical properties of matter

Abstract A new method of the perturbed angular γ – γ -correlation (PAC) measurements was developed using one HPGe detector only (1-PAC). For quantifying the perturbation factor, the ratio R γ 1 + γ 2 of the summing peak composed of two cascade γ -rays (the perturbation-affected parameter) to the summing peak composed of one γ -ray and one X-ray (the perturbation non-affected parameter) was used. This method was demonstrated for the radionuclides 111 In and 111m Cd, identifying the chemical status of the radionuclides in aqueous solutions.

Novel Radiolabeled Bisphosphonates for PET Diagnosis and Endoradiotherapy of Bone Metastases.

Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of 99mTc are predominantly used as SPECT tracers. In contrast to SPECT, PET offers a higher spatial resolution and, owing to the 68Ge/68Ga generator, an analog to the established 99mTc generator exists. Complexation of Ga(III) requires the use of chelators. Therefore, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclododecane-1,4,7-triacetic acid), and their derivatives, are ofte…

18F-labeling and evaluation of novel MDL 100907 derivatives as potential 5-HT2A antagonists for molecular imaging.

Abstract Introduction The serotonergic system, especially the 5-HT2A receptor, is involved in various diseases and conditions. It is a very interesting target for medicinal applications. Methods Two novel 5-HT2A tracers, namely, [ 18 F]DD-1 and the enantiomeric pure ( R )-[ 18 F]MH.MZ, were radiolabeled by 18 F-fluoroalkylation of the corresponding desmethyl analogue. In vitro binding autoradiography on rat brain slices was performed to test the affinity and selectivity of these tracers. Moreover, first μPET experiments of ( R )-[ 18 F]MH.MZ were carried out in Sprague-Dawley rats. Results [ 18 F]DD-1 ( K i =3.23 nM) and ( R )-[ 18 F]MH.MZ ( K i =0.72 nM) were 18 F-fluoroalkylated by the se…

Evaluation of the inverse electron demand Diels-Alder reaction in rats using a scandium-44-labelled tetrazine for pretargeted PET imaging

Background Pretargeted imaging allows the use of short-lived radionuclides when imaging the accumulation of slow clearing targeting agents such as antibodies. The biotin-(strept)avidin and the bispecific antibody-hapten interactions have been applied in clinical pretargeting studies; unfortunately, these systems led to immunogenic responses in patients. The inverse electron demand Diels-Alder (IEDDA) reaction between a radiolabelled tetrazine (Tz) and a trans-cyclooctene (TCO)-functionalized targeting vector is a promising alternative for clinical pretargeted imaging due to its fast reaction kinetics. This strategy was first applied in nuclear medicine using an 111In-labelled Tz to image TC…

HPMA-LMA copolymer drug carriers in oncology: an in vivo PET study to assess the tumor line-specific polymer uptake and body distribution.

Polymeric drug carriers aim to selectively target tumors in combination with protecting normal tissue. In this regard polymer structure and molecular weight are key factors considering organ distribution and tumor accumulation of the polymeric drug delivery system. Four different HPMA based copolymer structures (random as well as block copolymers with lauryl methacrylate as hydrophobic block) varying in molecular weight, size and resulting architecture were analyzed in two different tumor models (AT1 prostate carcinoma and Walker-256 mammary carcinoma) in vivo. Polymers were labeled with (18)F and organ/tumor uptake was followed by μPET imaging and ex vivo biodistribution. Vascular permeabi…

Produktion von PET-Radiopharmaka für den klinischen Gebrauch am Beispiel des MVZ-DTZ Berlin

PET-Radiopharmaka gehoren heute zum Repertoire der modernen Nuklearmedizin, auch wenn die Verfugbarkeit dieser Verbindungen fur den niedergelassenen Nuklearmediziner in mehrfacher Hinsicht auserordentlich eingeschrankt ist. Die Verfugbarkeit wird mit dem Inkrafttreten der 15. Novelle des AMG neu geregelt. Durch das Wegfallen des ehemaligen § 4a Satz 1 Nr. 3 fallen Herstellung und Anwendung dieser Praparationen nun unter den Geltungsbereich des AMG und die damit verbundenen Tatigkeiten sind nach § 67 Abs. 2 bei der zustandigen Genehmigungsbehorde anzeigepflichtig. Aus der geschilderten Situation ergibt sich die Notwendigkeit der Entwicklung einer Eigenherstellung von Radiopharmaka unter Prax…

Net influx of plasma 6-[18F]fluoro-L-DOPA (FDOPA) to the ventral striatum correlates with prefrontal processing of affective stimuli.

Dopaminergic neurotransmission in the ventral and dorsal striatum interact with central processing of rewarding and reward-indicating stimuli, and may affect frontocortical-striatal-thalamic circuits regulating goal-directed behaviour. Thirteen healthy male volunteers were investigated with multimodal imaging, using the radioligand 6-[ 18 F]fluoro-L-DOPA (FDOPA) for positron emission tomography (PET) measurements of dopamine synthesis capacity, and also functional magnetic resonance imaging (fMRI) in a cognitive activation paradigm. We calculated the correlation between FDOPA net blood-brain influx (K app in ; ml/g/min) in the ventral and associative dorsal striatum and BOLD signal changes …

Radiolanthanides in Nuclear Medicine

PEGylation of HPMA-based block copolymers enhances tumor accumulation in vivo: a quantitative study using radiolabeling and positron emission tomography.

Abstract This paper reports the body distribution of block copolymers (made by controlled radical polymerization) with N-(2-hydroxypropyl)methacrylamide (HPMA) as hydrophilic block and lauryl methacrylate (LMA) as hydrophobic block. They form micellar aggregates in aqueous solution. For this study the hydrophilic/hydrophobic balance was varied by incorporation of differing amounts of poly(ethylene glycol) (PEG) side chains into the hydrophilic block, while keeping the degree of polymerization of both blocks constant. PEGylation reduced the size of the micellar aggregates (Rh = 113 to 38 nm) and led to a minimum size of 7% PEG side chains. Polymers were labeled with the positron emitter 18F,…

[68Ga]Ga-THP-Pam: A Bisphosphonate PET Tracer with Facile Radiolabeling and Broad Calcium Mineral Affinity

Calcium minerals such as hydroxyapatite (HAp) can be detected non-invasively in vivo using nuclear imaging agents such as [18F]NaF (available from cyclotrons), for positron emission tomography (PET) and 99mTc-radiolabelled bisphosphonates (BP; available from 99mTc generators for single photon emission computed tomography (SPECT) or scintigraphy). These two types of imaging agents allow detection of bone metastases (based on the presence of HAp) and vascular calcification lesions (that contain HAp and other calcium minerals). With the aim of developing a cyclotron-independent PET radiotracer for these lesions, with broad calcium mineral affinity and simple one-step radiolabelling, we develop…

A no-carrier-added 72Se/72As radionuclide generator based on distillation

Abstract Arsenic-72 is a positron emitting isotope with promising properties for syntheses of 72As-labelled radiopharmaceuticals for future application in positron emission tomography. This work describes the radiochemical separation of no-carrier-added 72Se from cyclotron irradiated germanium targets and the development of a 72Se/72As radionuclide generator, avoiding the addition of any selenium carrier. Using a vertical quartz tube device, no-carrier-added 72As is nearly quantitatively released from various chloride salt solutions containing 72Se within 10 min at a temperature of 100 °C in an HCl gas flow. The kinetics of the 72Se/72As isotope generator has been studied in relation to tem…

AAZTA5-squaramide ester competing with DOTA-, DTPA- and CHX-A″-DTPA-analogues: Promising tool for 177Lu-labeling of monoclonal antibodies under mild conditions

Abstract Background Combining the advantages of both cyclic and acyclic chelator systems, AAZTA (1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine) is well suited for complexation of various diagnostic and therapeutic radiometals such as gallium-68, scandium-44 and lutetium-177 under mild conditions. Due to its specificity for primary amines and pH dependent binding properties, squaric acid (SA) represents an excellent tool for selective coupling of the appropriate chelator to different target vectors. Therefore, the aim of this study was to evaluate radiolabeling properties of the novel bifunctional AAZTA5-SA being coupled to a model antibody (bevacizumab) i…

Ethanol-Based Post-processing of Generator-Derived 68Ga Toward Kit-Type Preparation of 68Ga-Radiopharmaceuticals

Post-processing by means of a cation-exchanger–based protocol is an efficient strategy for purification and concentration of generator-derived 68Ga. It ensures the removal of 68Ge before 68Ga-radiopharmaceutical preparation and high labeling yields of 68Ga-labeled radiopharmaceuticals for routine medical application. Methods: In an effort to overcome the problem associated with acetone in the currently applied method, we have investigated the feasibility of replacing it with ethanol. The purification of 68Ga from coeluted metallic impurities (68Ge4+, Fe3+, Zn2+, and Ti4+) on various cation-exchange columns has been investigated with a variety of post-processing solutions. As a proof of prin…

An approach to the evaluation of the activity of the DNA repair enzyme O6-methylguanine-DNA-methyl-transferase in tumor tissue in vivo: syntheses of 6-benzyloxy-9-(2-[18F]fluoroethyl)-9H-purin-2-yl-amine and 6-benzyloxy-7-(2-[18F]fluoroethyl)-7H-purin-2-yl-amine

Abstract The resistance of tumor cells to the cytostatic activity of methylating and chloroethylating anticancer drugs is determined by the level of expression of the DNA repair protein O 6 -methylguanine-DNA-methyl-transferase (MGMT). The synthesis of labelled 6-benzyloxy-9H-purin-2-ylamine derivatives should hence allow a quantification of the MGMT status of tumor and non-target tissue in vivo. 6-benzyloxy-9-(2-fluoroethyl)-9H-purin-2-yl-amine and 6-benzyloxy-7-(2-fluoroethyl)-7H-purin-2-yl-amine were synthesized and evaluated in vitro, both showing an affinity of 1.8 μM. 6-benzyloxy-9-(2-[ 18 F]fluoroethyl)-9H-purin-2-yl-amine and 6-benzyloxy-7-(2-[ 18 F]fluoroethyl)-7H-purin-2-yl-amine …

Dinitrophenol-beinhaltende Glutamat-Urea-basierte PSMA-Liganden zur Diagnose und Therapie von Prostatakarzinomen

1st World Congress on Ga-68 and Peptide Receptor Radionuclide Therapy (PRRNT), June 23-26, 2011, Zentralklinik Bad Berka, Germany

A no-carrier-added 72Se/72As isotope generator

Siinznrary A no-carrier-added 72Se/72As generator has been developed for the isolation of 72As, relevant for eventual application in the syntheses of 72As-labelled radiophamaceuticals. Avoiding the addition of Se carrier and using a thennochromatographic destillation process, no-carrier-added 72As is nearly quantitatively released within 10 min. 72Se remains almost quantitatively (> 99.7%) in solution when a temperature of the separation process of 100°C is applied. Introdiiction Arsenic-72 is a positron emitting isotope with properties which are promising for eventual application in 72As-labelled radiopharmaceuticals. It has n positron emission rate of 88% and positron energies of EP+,,,,~…

High striatal occupancy of D2-like dopamine receptors by amisulpride in the brain of patients with schizophrenia.

The 'atypicality' of the antipsychotic drug, amisulpride, has been attributed to preferential extrastriatal binding. Previous investigations of striatal D2 receptor occupancy by amisulpride revealed conflicting results. The aim of this PET study was to measure the striatal occupancy by amisulpride and to correlate it with the corresponding drug plasma concentrations. Nine amisulpride-treated patients and 12 healthy volunteers serving as controls were studied with PET and [18F]desmethoxyfallypride. Occupancy values and plasma concentrations were nonlinearly fitted to an E max model. Results showed 43-85% (putamen) and 67-90% (caudate) D2-like receptor occupancy. Plasma amisulpride concentrat…

Electroosmotic effects in the determination of ion mobilities of carrier-free radionuclides in free aqueous electrolyte solutions

A device for on-line electromigration studies of radio-elements in free electrolytes has been tested by measuring the absolute individual ion mobilities of no-carrier-added single charged anions [99mTc]TcO4 - and [18F]F- and differently charged cations [137Cs]Cs+, [57Co]Co2+ and [241Am]Am3+ in inert aqueous electrolytes at 298.1 K. The observed ion mobilities were found to be influenced by electroosmosis in the migration tube. A relation to correct this effect is proposed. In addition, it was shown that the effect of electroosmosis may be suppressed by chemical treatment of the surface of the migration tube.

Synthesis of a technetium-99m labelledL-tyrosine derivative with thefac-99mTc(I)(CO)3-core using a simple kit-procedure

Summary The synthesis of a novel technetium-99m labelled derivative of l-tyrosine as a potential tumour imaging agent for nuclear medicine diagnosis is reported. The synthesis involved the labelling precursor fac-[ 99m Tc(OH2)(CO)3] + which was synthesized using the commercially available Isolink 1 -labelling kit and the tyrosine derivative O-(N,Nbis(carboxymethyl)aminoethyl)-l-tyrosine trifluoroacetate. The labelled compound O( 99m Tc(I)-tricarbonyl-N,N-bis(carboxymethyl)aminoethyl)-l-tyrosine was obtained in a radiochemical yield of 70–80% within 60 min with a radiochemical purity greater than 98% without any HPLC purification step. Purification was achieved merely by solid phase extracti…

Synthesis and evaluation of fluorine-18 labeled glyburide analogs as β-cell imaging agents

Glyburide is a prescribed hypoglycemic drug for the treatment of type 2 diabetic patients. We have synthesized two of its analogs, namely N-[4-[beta-(2-(2'-fluoroethoxy)-5-chlorobenzenecarboxamido)ethyl]benzenesulfonyl]-N'-cyclohexylurea (2-fluoroethoxyglyburide, 8b) and N-[4-[beta-(2-(2'-fluoroethoxy)-5-iodobenzenecarboxamido)ethyl]benzenesulfonyl]-N'-cyclohexylurea (2-fluoroethoxy-5-deschloro-5-iodoglyburide, 8a), and their fluorine-18 labeled analogs as beta-cell imaging agents. Both F-18 labeled compound 8a and compound 8b were synthesized by alkylation of the corresponding multistep synthesized hydroxy precursor 4a and 4b with 2-[(18)F]fluoroethyl tosylate in DMSO at 120 degrees C for …

Comparison of different phosphorus-containing ligands complexing 68Ga for PET-imaging of bone metabolism

Abstract 99mTc-phosphonate structures are well established tracers for bone tumour imaging. Our objective was to investigate different 68Ga-labelled phosphonate ligands concerning labelling kinetics, binding to hydroxyapatite and bone imaging using μ-PET. Seven macrocyclic phosphorus-containing ligands and EDTMP were labelled in nanomolar scale with n.c.a. 68Ga in Na-HEPES buffer at pH∼4. Except for DOTP, all ligands were labelled with &gt;92% yield. Binding of the 68Ga-ligand complexes on hydroxyapatite was analysed to evaluate the effect of the number of the phosphorus acid groups on adsorption parameters. Adsorption of 68Ga-EDTMP and 68Ga-DOTP was &gt;83%. For the 68Ga-NOTA-phosphonates …

SYNTHESIS AND IN VITRO AFFINITIES OF VARIOUS MDL 100907 DERIVATIVES AS POTENTIAL 18F-RADIOLIGANDS FOR 5-HT2A RECEPTOR IMAGING WITH PET

Radiolabelled piperidine derivatives such as [(11)C]MDL 100907 and [(18)F]altanserin have played an important role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine MDL 100907 derivatives, possible to label with (18)F-fluorine, were synthesized to improve molecular imaging properties of [(11)C]MDL 100907. Their in vitro affinities to a broad spectrum of neuroreceptors and their lipophilicities were determined and compared to the clinically used reference compounds MDL 100907 and altanserin. The novel compounds MA-1 (53) and (R)-MH.MZ (56) show K(i)-values in the nanomolar range towards the 5-HT(2A) receptor and insignificant binding to other 5-HT…

Synthesis of [18F]-Fluoroethylfenoterol for imaging β2 receptor status in lung in vivo

5-(-{2-[4-(2-[18F]Fluoroethoxy)-phenyl]-l-methyl-ethylamino}-l-hydroxy-ethyl)-benzene-1, 3-diol ([18F]fluoroethylfenoterol) was synthesised from 4-(2-{benzyl-[2-(3,5-bis-benzyloxy-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-phenol using 2-[18F]fluoroethyltosylate (92% RCY) followed by reductive cleavage of the benzyl protecting groups. Preliminary in vitro tests showed [19F]fluoroethylfenoterol to be as potent in relaxation of lung tissue as fenoterol itself.

Instant kit preparation of 68Ga-radiopharmaceuticals via the hybrid chelator DATA: clinical translation of [68Ga]Ga-DATA-TOC

Purpose The widespread use of 68Ga for positron emission tomography (PET) relies on the development of radiopharmaceutical precursors that can be radiolabelled and dispensed in a simple, quick, and convenient manner. The DATA (6-amino-1,4-diazapine-triacetate) scaffold represents a novel hybrid chelator architecture possessing both cyclic and acyclic character that may allow for facile access to 68Ga-labelled tracers in the clinic. We report the first bifunctional DATA chelator conjugated to [Tyr3]octreotide (TOC), a somatostatin subtype 2 receptor (SST2)-targeting vector for imaging and functional characterisation of SSTR2 expressing tumours. Methods The radiopharmaceutical precursor, DATA…

Mild and efficient 64Cu labeling of perhydro-1, 4-diazepine derivatives for potential use with large peptides, proteins and antibodies

Abstract DATA (6-Amino-1,4-diazapine-triacetate) and AAZTA (6-Amino-1,4-diazapine-tetracetate) chelators represent a novel approach representing hybrid-chelates: possessing significant cyclic and acyclic character. It is believed that flexibility of the acyclic part facilitates rapid complexation, whilst the preorganized cyclic part minimizes the energy barrier to complexation and inhibits decomplexation processes. So far, these chelators have been used exclusively with 44Sc and 68Ga only. Recent results with natCu predict high stabilities for Cu-AAZTA, yet no radioactive labeling of AAZTA or DATA with 64Cu or any additional radioactive isotope has been reported. We present the one pot synt…

Limiting transport properties of lanthanide and actinide ions in pure water

Summary The limiting transport properties, i.e. the limiting ionic conductivity (λ°) and the limiting diffusion coefficient (D°), of lanthanide and actinide ions at 298.15K have been calculated by means of the microscopic version of the Stokes–Einstein law involving (i) the effective charge and the ionic radius of the ions and (ii) the ion micro-viscosity, i.e. the viscosity of the hydrated water molecules in the vicinity of the ion. The latter quantity was derived from the variation of the dynamic properties of the water molecules in the first hydration shell with the surface charge density of common mono-atomic cations of various charges. The obtained results were found to be consistent w…

An experimental comparison of the K- and L-Auger electron spectra generated in the decays of 140Nd and 111In

The low-energy electron spectra generated in the decay of 140Nd have been measured using a combined electrostatic spectrometer adjusted to the 4, 7, and 35 eV instrumental resolution. In order to estimate the therapeutic potential of low-energy electrons associated with the decay of 140Nd, similar experiments have been performed with 111In. Relative Auger electron intensity ratios per decay are: 111In(K-Auger)/140Nd(K-Auger)=1.47(12), 111In(L-Auger) /140Nd(L-Auger)=1.1(4), and 111In(L-Auger [2.8-7 keV])/140Nd(L-Auger [2.8-7 keV])=0.24(11). The obtained K-Auger group intensity ratios have been compared with results of calculations. The good agreement found for the experimental and estimated …

High opiate receptor binding potential in the human lateral pain system: A (FEDPN)PET study

Generator-based PET radiopharmaceuticals for molecular imaging of tumours: on the way to THERANOSTICS.

Generator-derived radionuclides for PET/CT imaging are promising for optimizing targeted radiotherapy by an individual patient-based approach, applying pre-therapeutic evaluation, as well as dosimetric calculations, and for measuring treatment response after radionuclide therapy.

A new method for radiochemical separation of arsenic from irradiated germanium oxide.

Abstract Radioarsenic labelled radiopharmaceuticals could be a valuable asset to Positron Emission Tomography (PET). In particular, the long half-lives of 72 As ( T 1/2 =26 h) and 74 As ( T 1/2 =17.8 d) allow to investigate slow physiological or metabolical processes, like the enrichment and distribution of antibodies in tumor tissue. This work describes the direct production of no-carrier-added (nca) arsenic isotopes *As, with *=71, 72, 73, 74 or 77, the reaction to [*As]AsI 3 and its radiochemical separation from the irradiated solid germanium oxide via polystyrene-based solid-phase extraction. The germanium oxide target, irradiated at a cyclotron or a nuclear reactor, is dissolved in con…

Development of a [177Lu]BPAMD Labeling Kit and an Automated Synthesis Module for Routine Bone Targeted Endoradiotherapy

Painful bone lesions, both benign and metastatic, are often managed using conventional analgesics. However, the treatment response is not immediate and is often associated with side-effects. Radionuclide therapy is used for pain palliation in bone metastases as well as some benign neoplasms. Endoradiotherapy has direct impact on the pain-producing bone elements, and hence, response is significant, with minimal or no side-effects. A new potential compound for endoradiotherapy is [(177)Lu]BPAMD. It combines a highly affine bisphosphonate, covalently bridged with DOTA through an amide bond, with the low-energy β(-) emitting therapeutic radiolanthanide (177)Lu. For routine chemical application,…

Long-term biodistribution study of HPMA- ran -LMA copolymers in vivo by means of 131 I-labeling

Abstract Background For the evaluation of macromolecular drug delivery systems suitable pre-clinical monitoring of potential nanocarrier systems is needed. In this regard, both short-term as well as long-term in vivo tracking is crucial to understand structure-property relationships of polymer carrier systems and their resulting pharmacokinetic profile. Based on former studies revealing favorable in vivo characteristics for 18 F–labeled random (ran) copolymers consisting of N-(2-hydroxypropyl)methacrylamide (HPMA) and lauryl methacrylate (LMA) – including prolonged plasma half-life as well as enhanced tumor accumulation – the presented work focuses on their long-term investigation in the li…

In vitro affinities of various halogenated benzamide derivatives as potential radioligands for non-invasive quantification of D(2)-like dopamine receptors.

Abstract Benzamide derivatives as radiotracers have played an important role in diagnosing malfunction in dopaminergic neurotransmission. A variety of halogenated and two unsubstituted benzamide derivatives were synthesised and their in vitro affinities to dopaminergic, serotonergic and adrenergic receptors and their lipophilicities were determined. As references IBZM (3), raclopride (4) and FLB457 (5) were tested as well. The two iodinated compounds NAE (27) and NADE (28) displayed Ki values of 0.68 and 14 nM for the D2 receptor. The well-established radiotracers FP (1) and DMFP (2) showed affinities in the same range as did the brominated compounds NABrE (29) and NABrDE (30). The log D7.4…

Changes in the expression of neurotransmitter receptors in Parkin and DJ-1 knockout mice – A quantitative multireceptor study

Parkinson's disease (PD) is a well-characterized neurological disorder with regard to its neuropathological and symptomatic appearance. At the genetic level, mutations of particular genes, e.g. Parkin and DJ-1, were found in human hereditary PD with early onset. Neurotransmitter receptors constitute decisive elements in neural signal transduction. Furthermore, since they are often altered in neurological and psychiatric diseases, receptors have been successful targets for pharmacological agents. However, the consequences of PD-associated gene mutations on the expression of transmitter receptors are largely unknown. Therefore, we studied the expression of 16 different receptor binding sites …

68Ga- und 177Lu-markierte Bisphosphonate als Knochenmetastasen-Theranostika

Der erhohte Metabolismus der Knochenmatrix kann zum einen mit der SPECT- und zum anderen mit der PET-Technik visualisiert werden. Als SPECT-Nuklid wird uberwiegend 99 mTc in Form von [99mTc]Bisphosphonat-Komplexen verwendet. Die PET bietet im Gegensatz zur SPECT eine hohere lokale und temporale Auflosung. Mit dem 68Ge/68Ga-Generatorsystem existiert ein mittlerweile bewahrtes PET-Pendant zum etablierten 99mTc-Generator. Neuartige Bisphosphonate (BP) in Kombination mit makrozyklischen Chelatoren sind derzeit weltweit Gegenstand der Forschung. Zur Komplexierung von Ga(III) werden haufig DOTA und NOTA sowie deren Derivate verwendet. Speziell im Fall von DOTA-Derivaten bieten DOTA-BP die Moglich…

68Ge content quality control of 68Ge/68Ga-generator eluates and 68Ga radiopharmaceuticals – A protocol for determining the 68Ge content using thin-layer chromatography

(68)Ge breakthrough from a (68)Ge/(68)Ga-generator appears to be one of the most critical parameters for the routine clinical application of this generator and (68)Ga-radiopharmaceuticals. We report a TLC-based (thin-layer chromatography) protocol which allows the (68)Ge breakthrough of a generator to be determined within 1 h post-initial elution. The protocol can also be adapted to allow the (68)Ge content of a (68)Ga-radiopharmaceutical preparation to be determined prior to in vivo application.

A new method for the labelling of proteins with radioactive arsenic isotopes

Abstract  Radioarsenic labelled radiopharmaceuticals could be a valuable asset to positron emission tomography. In particular, the long half-lives of 72As ( T 1 / 2 = 26 h ) and 74As ( T 1 / 2 = 17.8 d ) allow to investigate slow physiological or metabolical processes, like the enrichment and distribution of monoclonal antibodies (mab) in tumour tissue. In this work, a new method for the labelling of proteins with various radioactive arsenic isotopes was developed. For this purpose, two proteins, namely a chimeric IgG3 monoclonal antibody, ch3G4, directed against anionic phospholipids, and Rituxan (Rituximab), were labelled as a proof of principle with no-carrier-added radioarsenic isotopes…

Evaluation of P-glycoprotein (abcb1a/b) modulation of [18F]fallypride in MicroPET imaging studies

[(18)F]Fallypride ([(18)F]FP) is an important and routinely used D2/D3 antagonist for quantitative imaging of dopaminergic neurotransmission in vivo. Recently it was shown that the brain uptake of the structurally related [(11)C]raclopride is modulated by P-glycoprotein (P-gp), an important efflux transporter at the blood-brain barrier. The purpose of this study was to determine whether the brain uptake of [(18)F]FP is influenced by P-gp. For examination of this possible modulation microPET studies were performed in a rat and a mouse model. Hence, [(18)F]FP was applied to Sprague Dawley rats, half of them being treated with the P-gp inhibitor cyclosporine A (CsA). In a second experimental s…

Koinzidenzspektrum-Analyse und Aktivitätsbestimmung mit Sc-44 zur Verbesserung der Quantifizierung

Macromol. Rapid Commun. 9-10/2011

44Ti/44Sc Generator and synthesis of 44Sc-DOTA-TOC

PET Imaging of the Impact of Extracellular pH and MAP Kinases on the p-Glycoprotein (Pgp) Activity

The functional activity of p-glycoprotein (Pgp) can be increased in vitro by an extracellular acidosis via activation of MAP kinases (p38, ERK1/2). In order to study these effects in vivo a new (68)Ga-labeled PET tracer was developed which serves as a substrate of the Pgp and therefore indirectly mirrors the Pgp activity. For in vivo studies, experimental tumors were imaged under acidic conditions (inspiratory hypoxia, injection of lactic acid) and during inhibition of MAP kinases in a μ-PET system. In vitro, [(68)Ga]MFL6.MZ showed an accumulation within the cells of about 20% which was increased to 30% by Pgp inhibition. In solid tumors a marked tracer uptake was observed showing spatial h…

Past, present and future of 68Ge/68Ga generators.

(68)Ga represents one of the very early radionuclides applied to positron emission tomography (PET) imaging at a time when even the wording PET itself was not established. Today it faces a renaissance in terms of new (68)Ge/(68)Ga radionuclide generators, sophisticated (68)Ga radiopharmaceuticals, and state-of-the-art clincial diagnoses via positron emission tomography/computed tomography (PET/CT). Thanks to the pioneering achievement of radiochemists in Obninsk, Russia, a new type of (68)Ge/(68)Ga generators became commercially available in the first years of the 21st century. Generator eluates based on hydrochloric acid provided "cationic" (68)Ga instead of "inert" (68)Ga-complexes, openi…

A no-carrier-added72Se/72As radionuclide generator based on solid phase extraction

Summary72As-labelled radiopharmaceuticals could be a valuable resource for Positron Emission Tomography (PET). In particular, the long half-life of72As (T1/2= 26 h) facilitates the observation of long-term physiological or metabolic processes, such as the enrichment and distribution of antibodies in tumor tissue. This work describes the primary radiochemical separation of no-carrier-added (nca)72Se from cyclotron irradiated germanium targets and the development of a polystyrene type solid-phase extraction based72Se/72As radionuclide generator, avoiding the addition of any selenium carrier. The irradiated germanium target is dissolved in HFconcand selenium is reduced with hydrazine dihydroch…

Synthesis of novel WAY 100635 derivatives containing a norbornene group and radiofluorination of [18F]AH1.MZ as a serotonin 5-HT1Areceptor antagonist for molecular imaging

5-HT1A receptors are involved in a variety of psychiatric disorders and in vivo molecular imaging of the 5-HT1A status represents an important approach to analyze and treat these disorders. We report herein the synthesis of three new fluoroethylated 5-HT1A ligands (AH1.MZ, AH2.MZ and AH3.MZ) as arylpiperazine derivatives containing a norbornene group. AH1.MZ (Ki= 4.2 nM) and AH2.MZ (Ki=30 nM) showed reasonable in vitro affinities to the 5-HT1A receptor, whereas AH3.MZ appeared to be non-affine toward the 5-HT1A receptor. The receptor profile of AH1.MZ and AH2.MZ showed selectivity within the 5-HT system. 18F-labelling via [18F]FETos to [18F]AH1.MZ was carried out in radiochemical yields of …

Improved column-based radiochemical processing of the generator produced 68Ga.

An improved chemical strategy for processing of the generator produced (68)Ga was developed based on processing of the original (68)Ge/(68)Ga generator eluate on a micro-column. Direct pre-concentration and purification of the eluted (68)Ga is performed on a cation-exchange resin in hydrochloric acid/acetone media. A supplementary step based on a second micro-column filled with a second resin allows direct re-adsorption of (68)Ga eluted from the cation exchanger. (68)Ga is finally striped from the second resin with a small volume of pure water. For this purpose a strong anion exchanger and a novel extraction chromatographic resin based on tetraalkyldiglycolamides are characterized. The stra…

Preliminary in vivo and ex vivo evaluation of the 5-HT2A imaging probe [18F]MH.MZ

Abstract Introduction The 5-HT 2A receptor is one of the most interesting targets within the serotonergic system because it is involved in a number of important physiological processes and diseases. Methods [ 18 F]MH.MZ, a 5-HT 2A antagonistic receptor ligand, is labeled by 18 F-fluoroalkylation of the corresponding desmethyl analogue MDL 105725 with 2-[ 18 F]fluoroethyltosylate ([ 18 F]FETos). In vitro binding experiments were performed to test selectivity toward a broad spectrum of neuroreceptors by radioligand binding assays. Moreover, first micro-positron emission tomography (μPET) experiments, ex vivo organ biodistribution, blood cell and protein binding and brain metabolism studies of…

Synthesis and evaluation of tritium labelled 10-methylgalanthamine iodide: a novel compound to examine the mechanism of interaction of galanthamine derivatives with the nicotinic acetylcholine receptors

Summary A new promising galanthamine derivative, 10-[ 3 H]methylgalanthamine iodide, was synthesized for binding studies to nicotinic acetylcholine receptors expressed in Torpedo electric ray electroplaques. Galanthamine was reacted with [ 3 H]methyl iodide to yield 10-[ 3 H]methylgalanthamine iodide with a radiochemical yield of >70% and a specific activity of 32 Ci/mmol after purification via solid phase extraction. To test the ligand properties of the radioligand, calcium imaging and electrophysiology of the non-radioactive analogue were performed to obtain an EC50 of 270 nM, a Hill coefficient of 1.9 and the induced cell current. Copyright # 2003 John Wiley & Sons, Ltd.

Diagnostik von ZNS-Erkrankungen mittels PET bzw. SPECT: Radiopharmazeutische Strategien und klinische Anwendungen

Radioaktiv markierte Molekule fur die nicht-invasive Darstellung biochemischer Funktionen haben seit etwa 25 Jahren betrachtlich zum Verstandnis normaler und gestorter Stoffwechselvorgange im Hirn beigetragen. In einigen Fallen hat dies dazu gefuhrt, dass 18F-markierte PET- bzw. 123I- und 99mTc-Radiodiagnostika ihren festen Platz bei der klinischen Diagnostik von Erkrankungen des Zentralen Nervensystems mittels der modernen tomographischen Techniken PET bzw. SPECT gefunden haben. Dies betrifft primar den Mb. Parkinson, die Epilepsie, zunehmend die Alzheimer Demenz, aber auch Hirntumore. Diese molekulare, neurochemische Diagnostik in vivo wird, in Konkurrenz zu etablierten klinischen Diagnos…

Additional file 1: of Evaluation of the inverse electron demand Diels-Alder reaction in rats using a scandium-44-labelled tetrazine for pretargeted PET imaging

Figure S1. HPLC radiochromatogram chromatogram of [44Sc]3 (Rt = 5.7 min). Figure S2. In vitro stability of [44Sc]3. (A) radio-TLC analysis of [44Sc]3 with 2 (lane 2) and without 2 (lane 1) following radiosynthesis. (B) Percent intact over time after incubation in saline (red circles) and human serum albumin (blue squares) for 0.5–24 h at 37 °C. Table S1. Summary of the uptake for [44Sc]3 in Wistar rats. Table S2. Summary of bone uptake values (4 h p.i.) and TCO:Tz ratios in individual rats. (DOC 275 kb)

In Vitro Evaluation of the Squaramide-Conjugated Fibroblast Activation Protein Inhibitor-Based Agents AAZTA5.SA.FAPi and DOTA.SA.FAPi

Recently, the first squaramide-(SA) containing FAP inhibitor-derived radiotracers were introduced. DATA5m.SA.FAPi and DOTA.SA.FAPi with their non-radioactive complexes showed high affinity and selectivity for FAP. After a successful preclinical study with [68Ga]Ga-DOTA.SA.FAPi, the first patient studies were realized for both compounds. Here, we present a new squaramide-containing compound targeting FAP, based on the AAZTA5 chelator 1,4-bis-(carboxylmethyl)-6-[bis-(carboxymethyl)-amino-6-pentanoic-acid]-perhydro-1,4-diazepine. For this molecule (AAZTA5.SA.FAPi), complexation with radionuclides such as gallium-68, scandium-44, and lutetium-177 was investigated, and the in vitro properties of…

Positron emission tomography in CNS drug discovery and drug monitoring.

Molecular imaging methods such as positron emission tomography (PET) are increasingly involved in the development of new drugs. Using radioactive tracers as imaging probes, PET allows the determination of the pharmacokinetic and pharmacodynamic properties of a drug candidate, via recording target engagement, the pattern of distribution, and metabolism. Because of the noninvasive nature and quantitative end point obtainable by molecular imaging, it seems inherently suited for the examination of a pharmaceutical’s behavior in the brain. Molecular imaging, most especially PET, can therefore be a valuable tool in CNS drug research. In this Perspective, we present the basic principles of PET, th…

New Frontiers in Cancer Imaging and Therapy Based on Radiolabeled Fibroblast Activation Protein Inhibitors: A Rational Review and Current Progress.

Over the past decade, the tumor microenvironment (TME) has become a new paradigm of cancer diagnosis and therapy due to its unique biological features, mainly the interconnection between cancer and stromal cells. Within the TME, cancer-associated fibroblasts (CAFs) demonstrate as one of the most critical stromal cells that regulate tumor cell growth, progression, immunosuppression, and metastasis. CAFs are identified by various biomarkers that are expressed on their surfaces, such as fibroblast activation protein (FAP), which could be utilized as a useful target for diagnostic imaging and treatment. One of the advantages of targeting FAP-expressing CAFs is the absence of FAP expression in q…

Synthesis and labeling of a squaric acid containing PSMA-inhibitor coupled to AAZTA5 for versatile labeling with 44Sc, 64Cu, 68Ga and 177Lu

Synthesis of C1-[18F]fluoroethylamnino asparagine for imaging cancer

C1-[18F]fluoroethylamino asparagine was synthesised from N1-t-boc C1-p-nitrophenol asparagine and the radiolabelled precursor [18F]flouroethylamine in a one-pot-synthesis. The yield of this synthesis was 22% referring to [18F]fluoride, including the removal of the protection groups. The in vivo tests are in progress.

Association of Low Striatal Dopamine D2Receptor Availability With Nicotine Dependence Similar to That Seen With Other Drugs of Abuse

All drugs of abuse induce a phasic dopamine release within the striatum that does not undergo habituation. Prolonged substance consumption impairs the natural function of the mesolimbic dopamine system, as shown by a decrease in the availability of striatal dopamine 2 (D(2)) receptors in patients suffering from cocaine, heroin, amphetamine, and alcohol dependence. However, it is unclear whether similar changes can also be observed in heavy-smoking nicotine-dependent smokers.In vivo D(2)/D(3) receptor availability was determined with [ (18)F]fallypride positron emission tomography in 17 heavy-smoking nicotine-dependent subjects and in 21 age-matched never-smoking comparison subjects. The smo…

Comparison of linear and hyperbranched polyether lipids for liposome shielding by 18F-radiolabeling and positron emission tomography

Multifunctional and highly biocompatible polyether structures play a key role in shielding liposomes from degradation in the bloodstream, providing also multiple functional groups for further attachment of targeting moieties. In this work hyperbranched polyglycerol (hbPG) bearing lipids with long alkyl chain anchor are evaluated with respect to steric stabilization of liposomes. The branched polyether lipids possess a hydrophobic bis(hexadecyl)glycerol membrane anchor for the liposomal membrane. hbPG was chosen as a multifunctional alternative to PEG, enabling the eventual linkage of multiple targeting vectors. Different hbPG lipids (Mn = 2900 and 5200 g mol-1) were examined. A linear bis(h…

Quantitative online isolation of 68Ge from 68Ge/68Ga generator eluates for purification and immediate quality control of breakthrough

The breakthrough of ⁶⁸Ge from a ⁶⁸Ge/⁶⁸Ga-generator is one of the most sensitive parameters in the context of the clinical application of ⁶⁸Ga-radiopharmaceuticals. The difficulty in its determination lies in the "spectroscopic invisibility" of ⁶⁸Ge within an excess of ⁶⁸Ga. The introduced method for determining the ⁶⁸Ge content of the ⁶⁸Ge/⁶⁸Ga-generator eluate involves the quantitative separation of ⁶⁸Ga from ⁶⁸Ge, using a cation-exchanger. The eluate contains ⁶⁸Ga free of ⁶⁸Ge, which can be determined immediately, i.e. prior to the application of the ⁶⁸Ga-radiopharmaceutical.

Neurotransmitter receptor density changes in Pitx3ak mice – A model relevant to Parkinson’s disease

Abstract Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by alterations of nigrostriatal dopaminergic neurotransmission. Compared to the wealth of data on the impairment of the dopamine system, relatively limited evidence is available concerning the role of major non-dopaminergic neurotransmitter systems in PD. Therefore, we comprehensively investigated the density and distribution of neurotransmitter receptors for glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine in brains of homozygous aphakia mice being characterized by mutations affecting the Pitx3 gene. This genetic model exhibits crucial hallmarks of PD on the ne…

68Ga-BPAMD: PET-imaging of bone metastases with a generator based positron emitter

Abstract Purpose Bone metastases are a serious aggravation for patients suffering from cancer. Therefore, early recognition of bone metastases is of great interest for further treatment of patients. Bisphosphonates are widely used for scintigraphy of bone lesions with 99m Tc. Using the 68 Ge/ 68 Ga generator together with a macroyclic bisphosphonate a comparable PET-tracer comes into focus. Procedures The bisphosphonate DOTA-conjugated ligand BPAMD was labelled with 68 Ga. [ 68 Ga]BPAMD was evaluated in vitro concerning binding to hydroxyapatite and stability. The tracer's in vivo accumulation was determined on healthy rats and bone metastases bearing animals by μ-PET. Results BPAMD was lab…

NODAPA-OH and NODAPA-(NCS)n: Synthesis, 68Ga-radiolabelling and in vitro characterisation of novel versatile bifunctional chelators for molecular imaging

This report concerns synthesis, (68)Ga-radiolabelling and stability data of 1,4,7-triazacyclononane-1,4-diacetic acid-7-p-isothio-cyanatophenyl-acetic acid (NODAPA-NCS), 1,4,7-triazacyclononane-1-acetic acid-4,7-di-p-isothiocyanatophenyl-acetic acid (NODAPA-(NCS)(2)) and 1,4,7-triazacyclononane-1,4-diacetic acid-7-p-hydroxyphenyl-acetic acid (NODAPA-OH), versatile bifunctional chelators with potential for molecular imaging. Protein binding and exemplified conjugation are also reported.

Synthesis of 131I-labeled glucose-conjugated inhibitors of O6-methylguanine-DNA methyltransferase (MGMT) and comparison with nonconjugated inhibitors as potential tools for in vivo MGMT imaging.

O 6 -Substituted guanine derivatives are powerful agents used for tumor cell sensitization by inhibition of the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT). To provide targeted accumulation of MGMT inhibitors in tumor tissue as well as tools for in vivo imaging, we synthesized iodinated C 8 -alkyl-linked glucose conjugates of 2-amino-6-(5-iodothenyl)-9H-purine (O 6 -(5-iodothenyl) guanine, ITG) and 2-amino-6-(3-iodobenzyloxy)-9H-purine (O 6 -(5-iodobenzyl) guanine, IBG). These compounds have MGMT inhibitor constants (IC 5 0 values) of 0.8 and 0.45 μM for ITGG and IBGG, respectively, as determined in HeLa S3 cells after 2-h incubation with inhibitor. To substantiate tha…

Efficient synthesis of 2-bromo-1-[18F]fluoroethane and its application in the automated preparation of 18F-fluoroethylated radiopharmaceuticals

An efficient synthesis of 2-bromo-1-[18F]fluoroethane from commercially available 1,2-dibromoethane and its integration into an automated preparation device was developed for the routine synthesis of 18F-fluoroethylated radiopharmaceuticals. The precursor 1,2-dibromoethane was reacted with the [18F]fluoride/Kryptofix®2.2.2./carbonate-complex in acetonitrile at 70°C for 3 minutes. The crude reaction mixture was diluted with water, loaded on a LiChrolute ®EN-cartridge, eluated with acetonitrile and passed through an Alumina ®B-cartridge. The method can provide 2-bromo-1-[18F]fluoroethane with 98% radiochemical purity completely free of 1, 2-dibromoethan within 10 min, thus avoiding a purifyin…

Radiochemical separation of no-carrier-added as produced via the process

The 176Yb(n,gamma)177Yb-beta(-)-->177Lu process was investigated to provide no-carrier-added (nca) 177Lu. The radiochemical separation of the 177Lu from the macro-amounts of the ytterbium target based on the cementation process, i.e. the selective extraction of Yb by Na(Hg) amalgam from Cl-/CH3COO- electrolytes, followed by a final cation exchange purification. The cementation separation process provides a decontamination factor of Yb(III) of 10(4), the cation exchange purification adding a decontamination factor of > 10(2). The nca 177Lu is available in radiochemically pure form despite the chemical similarity of the lanthanides with 75 +/- 5% overall separation yield within 4-5 h. It can …

Selective binding to monoamine oxidase A: in vitro and in vivo evaluation of (18)F-labeled β-carboline derivatives.

In this study we synthesized four different (18)F-labeling precursors for the visualization of the monoamino oxidase A using harmol derivatives. Whereas two are for prosthetic group labeling using [(18)F]fluoro-d2-methyl tosylate and 2-[(18)F]fluoroethyl-tosylate, the other three precursors are for direct nucleophilic (18)F-labeling. Additionally the corresponding reference compounds were synthesized. The syntheses of [(18)F]fluoro-d2-methyl-harmol and 2-[(18)F]fluoroethyl-harmol were carried out using harmol as starting material. For direct nucleophilic (18)F-labeling of the tracers carrying oligoethyled spacers (PEG), a toluenesulfonyl leaving group was employed. The radiolabeling, purifi…

HPMA Based Amphiphilic Copolymers Mediate Central Nervous Effects of Domperidone

In this study we give evidence that domperidone encapsulated into amphiphilic p(HPMA)-co-p(laurylmethacrylate) (LMA) copolymer aggregates is able to cross the blood-brain barrier, since it affected motor behaviour in animals, which is a sensitive measure for CNS actions. Carefully designed copolymers based on the clinically approved p(HPMA) were selected and synthesized by a combination of controlled radical polymerization and post-polymerization modification. The hydrodynamic radii (R(h) ) of amphiphilic p(HPMA)-co-p(LMA) alone and loaded with domperidone were determined by fluorescence correlation spectroscopy.

Additional file 1: of Instant kit preparation of 68Ga-radiopharmaceuticals via the hybrid chelator DATA: clinical translation of [68Ga]Ga-DATA-TOC

Table S1. Binding affinities of [natGa]Ga-DATA-TOC and [natGa]Ga-DOTA-TOC on hSST2/3/5, as determined during displacement of [125I-Tyr25]LTT-SS28 from transfected HEK293-hSST2/3/5 cell membranes; LTT-SS28 served as reference. Table S2. Uptake in terms of %IA of [68Ga]Ga-DATA-TOC or [68Ga]Ga-DOTA-TOC in selected organs of MPC-mCherry tumour-bearing female NMRI nu/nu mice 1 h p.i. (218 ± 57 MBq (11.2 nmol peptide/kg) and 441 ± 109 MBq (10.5 nmol peptide)/kg body weight, respectively; blocking after coinjection of 100 µg/mouse [Nal3]octreotide acetate)). Table S3. Radioactivity concentration in terms of SUV of [68Ga]Ga-DATA-TOC or [68Ga]Ga-DOTA-TOC in selected organs of MPC-mCherry tumour-bear…

On the consensus nomenclature rules for radiopharmaceutical chemistry – Reconsideration of radiochemical conversion

Radiochemical conversion is an important term to be included in the "Consensus nomenclature rules for radiopharmaceutical chemistry". Radiochemical conversion should be used to define reaction efficiency by measuring the transformation of components in a crude reaction mixture at a given time, whereas radiochemical yield is better suited to define the efficiency of an entire reaction process including, for example, separation, isolation, filtration, and formulation. (C) 2020 Elsevier Inc. All rights reserved.

Measurement of the laser resonance ionization efficiency for lutetium

Abstract The development of a highly efficient resonance ionization scheme for lutetium is presented. A laser ion source, based on the all-solid-state Titanium:sapphire laser system, was used at the 30 keV RISIKO off-line mass separator to characterize different possible optical excitation schemes in respect to their ionization efficiency. The developed laser resonance ionization scheme can be directly applied to the use at radioactive ion beam facilities, e. g. at the CERN-MEDICIS facility, for large-scale production of medical radioisotopes.