Cation exchange-based post-processing of 68Ga-eluate: A comparison of three solvent systems for labelling of DOTATOC, NO2APBP and DATAm

Interest in (68)Ga has led to a number of innovations for its provision suitable for clinical application. Several post-processing methods are available to reduce eluate volume and remove metal trace impurities. In this work three cation exchange resin based post-processing methods (acetone, ethanol and NaCl) have been compared, using three model precursors (DOTATOC, NO2AP(BP) and DATA(m)), in terms of labelling yield and reproducibility. The acetone and ethanol based methods provided greater reproducibility and yields that makes subsequent purification unnecessary.

ChemInform Abstract: Dimethylpyridin-4-ylamine-Catalyzed Alcoholysis of 2-Amino-N,N,N-trimethyl-9H-purin-6-ylammonium Chloride: An Effective Route to O6-Substituted Guanine Derivatives from Alcohols with Poor Nucleophilicity.

Bone targeting compounds for radiotherapy and imaging: *Me(III)-DOTA conjugates of bisphosphonic acid, pamidronic acid and zoledronic acid

Background Bisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases. Conjugates of bisphosphonates with macrocyclic chelators open new possibilities in bone targeted radionuclide imaging and therapy. Subsequent to positron emission tomography (PET) examinations utilizing 68Ga-labelled analogues, endoradiotheraphy with 177Lu-labelled macrocyclic bisphosphonates may have a great potential in the treatment of painful skeletal metastases. Methods Based on the established pharmaceuticals pamidronate and zoledronate two new DOTA-α-OH-bisphosphonates, DOTAPAM and DOTAZOL(MM1.MZ) were successfully synthesized. The ligands were labe…

[68Ga]Ga-DO2A-(OBu-l-tyr)2: Synthesis, 68Ga-radiolabeling and in vitro studies of a novel 68Ga-DO2A-tyrosine conjugate as potential tumor tracer for PET

The synthesis, (68)Ga-labeling and in vitro study of the novel tyrosine chelate derivative [(68)Ga]Ga-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid-4,10-di-(O-butyl)-l-tyrosine ([(68)Ga]Ga-DO(2)A-(OBu-l-tyr)(2)) as a potential tracer for imaging tumor metabolism by positron emission tomography (PET) is presented. This approach combines the biological amino acid transporter targeting properties of l-tyrosine with the outstanding availability of (68)Ga(III) via the (68)Ge/(68)Ga generator. In vitro studies utilizing the F98-glioblastoma cell line revealed specific uptake of [(68)Ga]Ga-DO2A-(OBu-l-tyr)(2) that was comparable to that of the reference O-(2-[(18)F]fluoroethyl)-l-tyrosine (FET)…

Studies towards the development of lipophilic bifunctional N3S3 chelators for 68Ga

Abstract The present study is concerned with a concept of charge-neutral, lipophilic, macrocyclic bifunctional chelators, suitable for the introduction of a gallium-68 label into small molecules. The synthesis of a novel bifunctional N3S3-type chelator, derived from 1,4,7-triazacyclononane, initial 68Ga-radiolabelling and the determination of stability and calculated lipophilicity of the compound are described. The 68Ga-labelled chelate was obtained in a maximum radiochemical yield of 93±5% after a reaction time of 2 min. It remained intact over 3 h in a DTPA-challenge and a transferrin challenge experiment, indicating sufficient stability for PET studies.

Novel Fibroblast Activation Protein Inhibitor-Based Targeted Theranostics for Radioiodine-Refractory Differentiated Thyroid Cancer Patients: A Pilot Study.

Background: This exploratory study was to assess clinical and safety data with a novel fibroblast activation protein inhibitor-based targeted theranostics as a salvage treatment option in radioiodi...

[68Ga]Ga-DATA5m.SA.FAPi PET/CT: Specific Tracer-uptake in Focal Nodular Hyperplasia and potential Role in Liver Tumor Imaging.

Tropane-derived11C-labelled and18F-labelled DAT ligands

Radiolabelling of cocaine-derived 3-phenyltropanes for dopamine transporter positron emission tomography with 18F and 11C is reviewed. Copyright © 2013 John Wiley & Sons, Ltd.

Bifunctional Gallium-68 Chelators: Past, Present, and Future

This article reviews the development of bifunctional chelates for synthesising (68)Ga radiopharmaceuticals. It structures the chelates into groups of macrocycles, nonmacrocycles, and chimeric derivatives. The most relevant bifunctional chelates are discussed in chelate structure, parameters of (68)Ga-labeling, and stability of the (68)Ga-chelate complexes. Furthermore those derivatives are included, where (67)Ga was applied instead of (68)Ga. A particular feature discussed is the ability of certain bifunctional chelate structures to function in kit-type preparation of the (68)Ga radiopharmaceuticals. Currently, nonmacrocyclic and chimeric derivates attract particular attention such as THP-d…

Efficient microwave-assisted direct radiosynthesis of [(18)F]PR04.MZ and [(18)F]LBT999: selective dopamine transporter ligands for quantitative molecular imaging by means of PET.

Abstract PR04.MZ 8-(4-fluoro-but-2-ynyl)-3- p -tolyl-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid methyl ester ( 1 ) and LBT999 8-(( E )-4-fluoro-but-2-enyl)-3b- p -tolyl-8-aza-bicyclo[3.2.1]octane-2β-carboxylic acid methyl ester ( 2 ) are selective dopamine reuptake inhibitors, derived from cocaine. Compounds 1 and 2 were labelled with fluorine-18 at their terminally fluorinated N-substituents employing microwave enhanced direct nucleophilic fluorination. K[ 18 F]F − Kryptofix ® 222 cryptate, tetrabutyl ammonium [ 18 F]fluoride and caesium [ 18 F]fluoride were compared as fluoride sources under conventional and microwave enhanced conditions. Fluorination yields were remarkably increased un…

Desferrioxamine as an appropriate chelator for 90Nb: Comparison of its complexation properties for M-Df-Octreotide (M=Nb, Fe, Ga, Zr)

The niobium-90 radioisotope ((90)Nb) holds considerable promise for use in immuno-PET, due to its decay parameters (t½ = 14.6h, positron yield=53%, Eß(+)(mean) = 0.35 MeV and Eß(+)(max) = 1.5 MeV). In particular, (90)Nb appears well suited to detect in vivo the pharmacokinetics of large targeting vectors (50-150 kDa). In order to be useful for immuno-PET chelators are required to both stabilize the radionuclide in terms of coordination chemistry and to facilitate the covalent attachment to the targeting vector. Different chelators were evaluated for this purpose in terms of radiolabelling efficiency and stability of the radiolabelled Nb(V) complex and in order to determine the most suitable…

Maturation of a Key Resource – The Germanium-68/Gallium-68 Generator: Development and New Insights

(68)Ge/(68)Ga radionuclide generators have been investigated for almost fifty years, since the cyclotron-independent availability of positron emitting (68)Ga via the (68)Ge/(68)Ga system had always attracted researches working in basic nuclear chemistry as well as radiopharmaceutical chemistry. However, it took decades and generations of research (and researchers) to finally reach a level of (68)Ge/(68)Ga radionuclide generator designs adequate to the modern requirements of radiometal labelling chemistry. Nevertheless, most of the existing commercial generator systems address aspects of (68)Ge breakthrough and safe synthesis of (68)Ga radiopharmaceuticals by adopting eluate post-processing …

Fibroblast activation protein inhibitor (FAPi) positive tumour fraction on PET/CT correlates with Ki-67 in liver metastases of neuroendocrine tumours

Abstract Aim Gallium-68-labelled inhibitors of the fibroblast activation protein (FAPi) enable positron emission tomography/computed tomography (PET/CT) imaging of fibroblast activation. We evaluated if [68Ga]Ga-DATA5m.SA.FAPi PET/CT is related to Ki-67 as a marker of tumour aggressiveness in patients with liver metastases of NET. Methods Thirteen patients with liver metastases of a histologically confirmed NET who underwent PET/CT with [68Ga]Ga-DATA5m.SA.FAPi, [18F]FDG and [68Ga]Ga-DOTA-TOC were retrospectively analyzed. PET-positive liver tumour volumes were segmented for calculation of volume, SUVmax and PET-positive tumour fraction (TF). PET parameters were correlated with Ki-67. Result…

Behavior of Actinium, Alkaline, and Rare Earth Elements in Sr-Resin/Mineral Acid Systems

In this work, the interactions between the divalent alkaline earth elements (AEE) (Sr, Ba, Ra), the trivalent rare earth elements (REE) (Ce-Lu, Y), and Ac(III) with Sr-resin were investigated in the presence of HNO3, HCl, HBr, HClO4, and HPF6. Distribution coefficients of these ions on the Sr-resin were determined under batch-loading conditions. Lastly, online column separations were performed to demonstrate the utility of these systems. Substantial differences in the behavior of the ions in solutions comprised of the five different acids were observed. These differences can partly be explained by a combination of ion exchange (primary) and extraction (solvation) mechanisms. From a practica…

ChemInform Abstract: 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 Tumor Tissue.

Relationship between dopamine D2 receptor occupancy, clinical response, and drug and monoamine metabolites levels in plasma and cerebrospinal fluid. A pilot study in patients suffering from first-episode schizophrenia treated with quetiapine.

Combining measurements of the monoamine metabolites in the cerebrospinal fluid (CSF) and neuroimaging can increase efficiency of drug discovery for treatment of brain disorders. To address this question, we examined five drug-naive patients suffering from schizophrenic disorder. Patients were assessed clinically, using the Positive and Negative Syndrome Scale (PANSS): at baseline and then at weekly intervals. Plasma and CSF levels of quetiapine and norquetiapine as well CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindole-acetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were obtained at baseline and again after at least a 4 week medication trai…

Evaluation of a novel monoclonal antibody against tumor-associated MUC1 for diagnosis and prognosis of breast cancer

There is still a great unmet medical need concerning diagnosis and treatment of breast cancer which could be addressed by utilizing specific molecular targets. Tumor-associated MUC1 is expressed on over 90 % of all breast cancer entities and differs strongly from its physiological form on epithelial cells, therefore presenting a unique target for breast cancer diagnosis and antibody-mediated immune therapy. Utilizing an anti-tumor vaccine based on a synthetically prepared glycopeptide, we generated a monoclonal antibody (mAb) GGSK-1/30, selectively recognizing human tumor-associated MUC1. This antibody targets exclusively tumor-associated MUC1 in the absence of any binding to MUC1 on health…

P-Glycoprotein Influence on the Brain Uptake of a 5-HT2A Ligand: [18F]MH.MZ

<i>Background/Aims:</i> The serotonergic system, especially the 5-HT<sub>2A</sub> receptor, is involved in various diseases and conditions. We have recently developed a new [<sup>18</sup>F]-5-HT<sub>2A</sub> receptor ligand using an analogue, MDL 100907, as a basis for molecular imaging with positron emission tomography. This tracer, [<sup>18</sup>F]MH.MZ, has been shown to be an adequate tool to visualize the 5-HT<sub>2A</sub> receptors in vivo. However, [<sup>18</sup>F]altanserin, similar in chemical structure, is a substrate of efflux transporters, such as P-glycoprotein (P-gp), of the blood-brain barrier…

Two-step radiosynthesis of [18F]FE-β-CIT and [18F]PR04.MZ

The cocaine-derived dopamine reuptake inhibitors FE-β-CIT (8-(2-fluoroethyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester) (1) and PR04.MZ(8-(4-fluorobut-2-ynyl)-3-p-tolyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester) (2) were labelled with (18)F-fluorine using a two-step route. 2-[(18)F]Fluoroethyltosylate and 4-[(18)F]fluorobut-2-yne-1-yl tosylate were used as labelling reagents, respectively. Radiochemically pure (>98%) [(18)F]FE-β-CIT and [(18)F]PRD04.MZ (32-86 GBq/µmol) were obtained after a synthesis time of 100 min in about 25% non-decay-corrected overall yield.

closo-borane conjugated regulatory peptides retain high biological affinity: synthesis of closo-borane conjugated Tyr(3)-octreotate derivatives for BNCT.

Despite the improvements in cancer therapy during the past years, high-grade gliomas and many other types of cancer are still extremely resistant to current forms of therapy. Boron neutron capture therapy (BNCT) provides a promising way to destroy cancer cells without damaging healthy tissue. However, BNCT in practice is still limited due to the lack of boron-containing compounds that selectively deliver boron to cancer cells. Since many neuroendocrine tumors show an overexpression of the somatostatin receptor, it was our aim to synthesize compounds that contain a large number of boron atoms and still show high affinity toward this transmembrane receptor. The synthetic peptide Tyr (3)-octre…

Squaric Acid-Based Radiopharmaceuticals for Tumor Imaging and Therapy.

Targeting vectors bound to a chelator represent a significant fraction of radiopharmaceuticals used nowadays for diagnostic and therapeutic purposes in nuclear medicine. The use of squaramides as coupling units for chelator and targeting vector helps to circumvent the disadvantages of several common coupling methods. This review gives an overview of the use of squaric acid diesters (SADE) as linking agents. It focuses on the conjugation of cyclic chelators, e.g., DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), as well as hybrid chelators like AAZTA5 (6-pentanoic acid-6-amino-1,4-diazepine tetracetic acid) or DATA5m (6-pentanoic acid-6-amino-1,4-diazapine-triacetate) to diff…

Retraction notice to “Relationship between dopamine D2 receptor occupancy, clinical response, and drug and monoamine metabolites levels in plasma and cerebrospinal fluid. A pilot study in patients suffering from first-episode schizophrenia treated with quetiapine” [J Psychiat Res 44 (2010) 754–759]

[177Lu]Lu-DOTA-zoledronate therapy - first application in a patient with primary osseous metastatic bronchial carcinoma.

Direct flow separation strategy, to isolate no-carrier-added 90Nb from irradiated Mo or Zr targets

Abstract 90Nb has an intermediate half-life of 14.6 h, a high positron branching of 53% and optimal β + emission energy of only E mean 0.35 MeV per decay. These favorable characteristics suggest it may be a potential candidate for application in immuno-PET. Our recent aim was to conduct studies on distribution coefficients for ZrIV and NbV in mixtures of HCl/H2O2 and HCl/oxalic acid for anion exchange resin (AG 1 × 8) and UTEVA resin to develop a “direct flow” separation strategy for 90Nb. The direct flow concept refers to a separation accomplished using a single eluent on multiple columns, effectively streamlining the separation process and increasing the time efficiency. Finally, we also …

Characterisation of [11C]PR04.MZ in Papio anubis baboon: A selective high-affinity radioligand for quantitative imaging of the dopamine transporter

N-(4-fluorobut-2-yn-1-yl)-2β-carbomethoxy-3β-(4′-tolyl)nortropane (PR04.MZ, 1) is a PET radioligand for the non-invasive exploration of the function of the cerebral dopamine transporter (DAT). A reliable automated process for routine production of the carbon-11 labelled analogue [11C]PR04.MZ ([11C]-1) has been developed using GMP compliant equipment. An adult female Papio anubis baboon was studied using a test–retest protocol with [11C]-1 in order to assess test–retest reliability, metabolism and CNS distribution profile of the tracer in non-human primates. Blood sampling was performed throughout the studies for determination of the free fraction in plasma (fP), plasma input functions and m…

The Renaissance of the 68Ge/68Ga Radionuclide Generator Initiates New Developments in 68Ga Radiopharmaceutical Chemistry

⁶⁸Ge/⁶⁸Ga radionuclide generators have been investigated for almost fifty years now, since the cyclotron-independent availability of positron emitting ⁶⁸Ga via the ⁶⁸Ge/⁶⁸Ga system had always attracted researches working in basic nuclear chemistry as well as radiopharmaceutical chemistry. However, it took decades and generations of research (and researchers) to finally approach a reliable level of ⁶⁸Ge/⁶⁸Ga generator designs, adequate to the modern requirements of radiometal labeling chemistry. ⁶⁸Ga radiopharmacy now is awaking from a sort of hibernation. The exciting perspective for the ⁶⁸Ge/⁶⁸Ga generator, now - more than ever, asks for systematic chemical, radiochemical, technological an…

Scandium-44: Benefits of a Long-Lived PET Radionuclide Available from the 44Ti/44Sc Generator System

(44)Ti/(44)Sc radionuclide generators are of interest for molecular imaging. The 3.97 hours half-life of (44)Sc and its high positron branching of 94.27% may stimulate the application of (44)Sc-labeled PET radiopharmaceuticals. This review describes the current status of (44)Ti production, (44)Ti/(44)Sc radionuclide generator development, post-processing of generator eluates towards medical application, identification of ligands adequate to Sc(III) co-ordination chemistry, proof-of-principle labeling of (44)Sc-DOTA-octreotides, investigation of in vitro and in vivo parameters, and initial applications for molecular imaging - both in small animals and humans.

Spectroscopic, radiochemical, and theoretical studies of the Ga3+-N-2-hydroxyethyl piperazine-N'-2-ethanesulfonic acid (HEPES buffer) system: evidence for the formation of Ga3+ - HEPES complexes in (68) Ga labeling reactions.

Recent reports have claimed a superior performance of HEPES buffer in comparison to alternative buffer systems for 67/68 Ga labeling in aqueous media. In this paper we report spectroscopic (1H and 71 Ga NMR), radiochemical, mass spectrometry and theoretical modeling studies on the Ga3+/HEPES system (HEPES = N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid) performed with the aim of elucidating a potential contribution of HEPES in the 68/67 Ga radiolabeling process. Our results demonstrate that HEPES acts as a weakly but competitive chelator of Ga3+ and that this interaction depends on the relative Ga3+: HEPES concentration. A by-product formed in the labeling mixture has been identified …

Preliminary assessment of the imaging capability of the YAP–(S)PET small animal scanner in neuroscience

The new and fully engineered version of the YAP–(S)PET small animal scanner has been tested at the University of Mainz for preliminary assessment of its imaging capability for studies related to neuropharmacology and psychiatry. The main feature of the scanner is the capability to combine PET and SPECT techniques. It allows the development of new and interesting protocols for the investigation of many biological phenomena, more effectively than with PET or SPECT modalities alone. The scanner is made up of four detector heads, each one composed of a 4 � 4c m 2 of YAlO3:Ce (or YAP:Ce) matrix, and has a field of view (FOV) of 4 cm axially � 4c m + transaxially. In PET mode, the volume resoluti…

Structure and stability of hexadentate complexes of ligands based on AAZTA for efficient PET labelling with gallium-68

Pre-organised tricarboxylate ligands based on 6-amino-perhydro-1,4-diazepine bind (68)Ga rapidly and selectively in acetate buffer at pH 4 to 7, forming kinetically stable complexes suitable for use in PET imaging.

A combined 148Gd/244Cm source for energy calibration of α-spectrometers

For high-resolution alpha-particle spectroscopy, detector calibration sources of highest performance are required concerning thickness and homogeneity. In addition, the alpha-emitting radionuclides must have adequate half-lives and alpha-emission energies. This paper describes a new type of alpha-emitting calibration source, represented by a mixture of 148Gd and 244Cm. This system covers an alpha-energy range from 3.18 MeV (148Gd) to 5.76 and 5.80 MeV (244Cm). The source has been prepared by electrolytic deposition and has good performance in terms of thickness and homogeneity.

Validation of (68)Ge/(68)Ga generator processing by chemical purification for routine clinical application of (68)Ga-DOTATOC.

Abstract Introduction Imaging of somatostatin receptor expressing tumours has been greatly enhanced by the use of 68 Ga-DOTATOC and PET/CT. Methods In this work, a purification method for the 68 Ge/ 68 Ga generator eluate and a method to produce 68 Ga-DOTATOC suitable for clinical use were evaluated. The generator eluate was purified and concentrated on a cation-exchange cartridge in HCl/acetone media. The efficacy of this procedure in eliminating metal impurities from the 68 Ga solution was investigated by ICP-MS. The radiotracer quality was evaluated by radio-TLC, GC and γ-ray spectrometry. Results 68 Ga-DOTATOC preparations ( n =33) were carried out with a mean synthesis yield of 59.3±2.…

44Sc-DOTA-BN[2-14]NH2 in comparison to 68Ga-DOTA-BN[2-14]NH2 in pre-clinical investigation. Is 44Sc a potential radionuclide for PET?

In the present study we demonstrate the in vitro and in vivo comparison of the (44)Sc and (68)Ga labeled DOTA-BN[2-14]NH(2). (44)Sc is a positron emitter with a half life of 3.92 h. Hence it could be used for PET imaging with ligands requiring longer observation time than in the case of (68)Ga.The binding affinity of (nat)Sc-DOTA-BN[2-14]NH(2) and (nat)Ga-DOTA-BN[2-14]NH(2) to GRP receptors was studied in competition to [(125)I-Tyr(4)]-Bombesin in the human prostate cancer cell line PC-3. A preliminary biodistribution in normal rats was performed, while first microPET images were assessed in male Copenhagen rats bearing the androgen-independent Dunning R-3327-AT-1 prostate cancer tumor.The …

Separation of 90Nb from zirconium target for application in immuno-PET

Abstract Fast progressing immuno-PET asks to explore new radionuclides. One of the promising candidates is 90Nb. It has a half-life of 14.6 h that allows visualizing and quantifying biological processes with medium and slow kinetics, such as tumor accumulation of antibodies and antibodies fragments or drug delivery systems and nanoparticles. 90Nb exhibits a positron branching of 53% and an average kinetic energy of emitted positrons of E mean =0.35 MeV. Currently, radionuclide production routes and Nb V labeling techniques are explored to turn this radionuclide into a useful imaging probe. However, efficient separation of 90Nb from irradiated targets remains in challenge. Ion exchange based…

Biodistribution and post-therapy dosimetric analysis of [177Lu]Lu-DOTAZOL in patients with osteoblastic metastases: first results

Abstract Background Preclinical biodistribution and dosimetric analysis of [177Lu]Lu-DOTAZOL suggest the bisphosphonate zoledronate as a promising new radiopharmaceutical for therapy of bone metastases. We evaluated biodistribution and normal organ absorbed doses resulting from therapeutic doses of [177Lu]Lu-DOTAZOL in patients with metastatic skeletal disease. Method Four patients with metastatic skeletal disease (age range, 64–83 years) secondary to metastatic castration-resistant prostate carcinoma or bronchial carcinoma were treated with a mean dose of 5968 ± 64 MBq (161.3 mCi) of [177Lu]Lu-DOTAZOL. Biodistribution was assessed with serial planar whole body scintigraphy at 20 min and 3,…

Orthogonal Click Conjugation to the Liposomal Surface Reveals the Stability of the Lipid Anchorage as Crucial for Targeting

Synthetic access to multiple surface decorations are a bottleneck in the development of liposomes for receptor mediated targeting. This opens a complex multiparameter space, exploration of which is severely limited in terms of sample numbers and turnaround times. Here, we unlock this technological barrier by a combination of a milligram-scale liposome formulation using dual centrifugation and orthogonal click chemistry on the liposomal surface. Application of these techniques to conceptually new amphiphilic compounds, which feature norbornene and alkyne groups at the apex of sterically stabilizing, hyperbranched polyglycerol moieties, revealed a particular influence of the membrane anchor o…

A methodical 68Ga-labelling study of DO2A-(butyl- l-tyrosine)2 with cation-exchanger post-processed 68Ga: practical aspects of radiolabelling

Positron emission tomography (PET) with 68Ga is a fast-growing field in molecular imaging, both in research and in clinical routine. The availability of 68Ga via the 68Ge/68Ga radionuclide generator facilitates the development and production of radiopharmaceuticals independent of a cyclotron. The presented work shows a complete 68Ga labelling study exemplified on [68Ga]DO2A-(butyl- l-tyrosine)2, a potential tumour tracer for PET. A methodical sequence is followed to optimize the 68Ga-labelling reaction. Practical aspects are described and the different parameters contributing to the labelling yield are demonstrated. The influence of temperature, time, amount of labelling precursor and pH va…

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 ?-Cell Imaging Agent.

Radiolabeling of DOTATOC with the long-lived positron emitter 44Sc.

Abstract The positron-emitting radionuclide 44 Sc with a half-life of 3.97 h and a β + branching of 94.3% is of potential interest for clinical PET. As so far it is available from a 44 Ti/ 44 Sc generator in Mainz, where long-lived 44 Ti decays to no-carrier-added (nca) 44 Sc. The 44 Sc is a trivalent metal cation and should be suitable for complexation with many well established bifunctional chelators conjugated to peptides or other molecular targeting vectors. Thus, the aim of this work was to investigate the potential of 44 Sc for labeling of DOTA-conjugated peptides. DOTA-D-Phe 1 -Tyr 3 -octreotide (DOTATOC) was used as a model molecule to study and optimize labeling procedure. Reaction…

The DAT ligand [(18)F]PR17.MZ mirrors the in vivo pharmacokinetic profile of [(11)C]cocaine with significantly improved monoamine transporter selectivity.

Ex vivo and in vivo evaluation of [18F]PR04.MZ in rodents: a selective dopamine transporter imaging agent.

N-4-Fluorobut-2-yn-1-yl-2beta-carbomethoxy-3beta-phenyltropane (PR04.MZ) has been developed as dopamine transporter (DAT) ligand for molecular imaging. It contains a terminally fluorinated, conformationally constrained nitrogen substituent that is well suited for the introduction of fluorine-18. The present report describes the pharmacological characterisation of [18F]PR04.MZ. The ligand shows an IC50 value of 2 nM against human DAT, whereas the IC50 value against human serotonin transporter and human noradrenalin transporter are lower (110 nM and 22 nM, respectively). Furthermore, its ex vivo organ distribution, its binding profile in the rat brain and reversibility of binding were examine…

Synthesis and radiosynthesis of N5-[18F]fluoroethyl-Pirenzepine and its metabolite N5-[18F]fluoroethyl-LS 75

The well established M1 selective muscarinergic antagonist Pirenzepine 11-[2-(4-methyl-piperazin-1-yl)-acetyl]-5,11-dihydro-benzo[e]pyrido[3,2-b][1,4]diazepin-6-one (1) exhibits an unusual behaviour in vivo, which cannot be explained with M1 antagonism exclusively. One of the aspects discussed is a specific interaction with poly ADP-ribose polymerase (PARP-1). 1 undergoes metabolism to form LS 75 5,11-dihydro-benzo[e]pyrido[3,2-b][1,4]diazepin-6-one (2). In order to study deviations in Pirenzepine efficacy from pure M1 binding in vivo using PET, appropriate positron emitter labelled analogues of 1 and 2 were synthesised. Non-radioactive reference compounds 3 and 4 were tested for PARP-1 inh…

Labeling and preliminary in vivo assessment of niobium-labeled radioactive species: A proof-of-concept study.

Abstract The application of radionuclide-labeled biomolecules such as monoclonal antibodies or antibody fragments for imaging purposes is called immunoscintigraphy . More specifically, when the nuclides used are positron emitters, such as zirconium-89, the technique is referred to as immuno-PET . Currently, there is an urgent need for radionuclides with a half-life which correlates well with the biological kinetics of the biomolecules under question and which can be attached to the proteins by robust labeling chemistry. 90 Nb is a promising candidate for in vivo immuno-PET , due its half-life of 14.6h and low β + energy of E mean =0.35MeV per decay. 95 Nb on the other hand, is a convenient …

Automated GMP production of [11C]PR04.MZ via the captive solvent method and PET studies in non-human primates: A promising tracer for extrastriatal DAT imaging

Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

Abstract Background Fibroblast activation protein (FAP) is a proline selective serine protease that is overexpressed in tumor stroma and in lesions of many other diseases that are characterized by tissue remodeling. In 2014, a most potent FAP-inhibitor (referred to as UAMC1110) with low nanomolar FAP-affinity and high selectivity toward related enzymes such as prolyl oligopeptidase (PREP) and the dipeptidyl-peptidases (DPPs): DPP4, DPP8/9 and DPP2 were developed. This inhibitor has been adopted recently by other groups to create radiopharmaceuticals by coupling bifunctional chelator-linker systems. Here, we report squaric acid containing bifunctional DATA5m and DOTA chelators relied on UAMC…

Nb-90 - a potential PET nuclide: production and labeling of monoclonal antibodies

Abstract Fast progressing immuno-PET gives reasons to develop new potential medium-long and long-lived radioisotopes. One of the promising candidates is 90Nb. It has a half-life of 14.6 h, which allows visualizing and quantifying processes with medium and slow kinetics, such as tumor accumulation of antibodies and antibodies fragments or polymers and other nanoparticles. 90Nb exhibits a high positron branching of 53% and an optimal energy of β + emission of E mean=0.35 MeV only. Consequently, efficient radionuclide production routes and NbV labeling techniques are required. 90Nb was produced by the 90Zr(p,n) 90Nb nuclear reaction on natural zirconium targets. No-carrier-added (n.c.a.) 90Nb …

Behavior of Actinium, Alkaline, and Rare Earth Elements in Sr-Resin/Mineral Acid Systems

In this work, the interactions between the divalent alkaline earth elements (AEE) (Sr, Ba, Ra), the trivalent rare earth elements (REE) (Ce-Lu, Y), and Ac(III) with Sr-resin were investigated in the presence of HNO3, HCl, HBr, HClO4, and HPF6. Distribution coefficients of these ions on the Sr-resin were determined under batch-loading conditions. Lastly, online column separations were performed to demonstrate the utility of these systems. Substantial differences in the behavior of the ions in solutions comprised of the five different acids were observed. These differences can partly be explained by a combination of ion exchange (primary) and extraction (solvation) mechanisms. From a practica…

Approaching ‘kit-type’ labelling with 68Ga : the DATA chelators.

The DATA chelators are a novel class of tri-anionic ligands based on 6-amino-1,4-diazepine-triacetic acid, which have been introduced recently for the chelation of (68)Ga. Compared with macrocyclic chelators based on the cyclen scaffold (i.e., DOTA, DO3A, and DO2A derivatives), DATA chelators undergo quantitative radiolabelling more rapidly and under milder conditions. In this study, a systematic evaluation of the labelling of four DATA chelators--DATA(M), DATA(P), DATA(Ph), and DATA(PPh)--with (68)Ga is presented. The results highlight the extraordinary potential of this new class of chelators for application in molecular imaging using (68)Ga positron emission tomography (PET).

Novel bifunctional DATA chelator for quick access to site-directed PET 68Ga-radiotracers: preclinical proof-of-principle with [Tyr3]octreotide

Molecular imaging of tumors with the PET radionuclide 68Ga has gained momentum in clinical oncology due to the expanding availability of commercial 68Ge/68Ga-generators in combination with state-of-the-art PET/CT and PET/MRI hybrid imaging systems. Concurrently, interesting peptide-based or small-size vectors have been developed for theranostic use in cancer patients. Owing to the short half-life of 68Ga (t1/2 = 67.7 min) and the sensitivity of many targeting biomolecules, labeling and kit reconstitution in mild conditions allowing for quick access to ready-for-injection PET-tracers are highly desirable. The novel DATA ((6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate) chelator pre…

Prediction of Normal Organ Absorbed Doses for [177Lu]Lu-PSMA-617 Using [44Sc]Sc-PSMA-617 Pharmacokinetics in Patients With Metastatic Castration Resistant Prostate Carcinoma

In vivo pharmacokinetic analysis of [Sc]Sc-PSMA-617 was used to determine the normal organ-absorbed doses that may result from therapeutic activity of [Lu]Lu-PSMA-617 and to predict the maximum permissible activity of [Lu]Lu-PSMA-617 for patients with metastatic castration-resistant prostate carcinoma. Methods Pharmacokinetics of [Sc]Sc-PSMA-617 was evaluated in 5 patients with metastatic castration-resistant prostate carcinoma using dynamic PET/CT, followed by 3 static PET/CT acquisitions and blood sample collection over 19.5 hours, as well as urine sample collection at 2 time points. Total activity measured in source organs by PET imaging, as well as counts per milliliter measured in bloo…

Potential use of 68Ga-apo-transferrin as a PET imaging agent for detecting Staphylococcus aureus infection.

Abstract Introduction 67 Ga citrate has been extensively used to detect infection and inflammation since 1971. However, its clinical utility is compromised due to several limitations. The present project explored whether 68 Ga- apo -transferrin ( 68 Ga-TF), when prepared in vitro, is a useful agent for positron emission tomography (PET) imaging of bacterial infection. Methods An infection was induced in male Wistar rats by injecting 5×10 5 CFU units of Staphyococcus aureus in the right thigh muscle. 68 Ga-TF was synthesized by mixing 68 GaCl 3 with apo -transferrin (TF, 2 mg) in sodium carbonate (0.1 M, pH 7.0) and incubating at 40°C for 1 h. Animals were injected with 10–15 MBq of 68 Ga-TF…