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.

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 …

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…

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 …

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…

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…

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

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…

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…

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,…

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…

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…

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…

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.

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…

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.