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      Validation of HPLC method for the determination of chemical andradiochemical purity of a 68Ga-labelled EuK-Sub-kf-(3-iodo-y-) DOTAGA

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          Abstract

          The prostate-specific membrane antigen (PSMA) represents an ideal biomarker for molecular imaging. Various PSMA-targeted radioligands are available for prostate cancer imaging. In this study, labeling of PSMA I&T with 68Ga, as well as validation of the radiochemical purity of the synthesis product by reverse phase radio high-performance liquid chromatography (HPLC) method are intended. Since the standard procedure for the quality control (QC) was not available, definition of chemical and radiochemical purity of 68Ga-PSMA I&T was carried out according to the Q2 (R1) ICH guideline. The standard QC tests were analyzed with Scintomics 8100 radio-HPLC system equipped with a radioactivity detector. The method was evaluated in terms of linearity, precision and accuracy, LOQ, robustness parameters, and specificity. To assess the radiochemical and chemical purity of 68Ga-PSMA I&T, the developed method was validated to apply safely to patients. An excellent linearity was found between 1μg/mL and 30 μg/mL, with a limit of detection and limit of quantitation of 0.286 μg/mL and 0.866 μg/mL, respectively for 68Ga-PSMA I&T. The recovery was 96.8 ± 3.8%. The quality control of the final product was performed many times with validated radio-HPLC method and was found to comply with ICH requirements, thus demonstrating the accuracy and robustness of the method for routine clinical practice.

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          Expression of the prostate-specific membrane antigen.

          Stuart J. Corr, W. Heston, Lydia Powell … (1994)
          We have recently cloned a 2.65-kilobase complementary DNA (cDNA) encoding the prostate-specific membrane antigen (PSM) recognized by the 7E11-C5.3 anti-prostate monoclonal antibody. Immunohistochemical analysis of the LNCaP, DU-145, and PC-3 prostate cancer cell lines for PSM expression using the 7E11-C5.3 antibody reveals intense staining in the LNCaP cells with no detectable expression in both the DU-145 and PC-3 cells. Coupled in vitro transcription/translation of the 2.65-kilobase full-length PSM cDNA yields an M(r) 84,000 protein corresponding to the predicted polypeptide molecular weight of PSM. Posttranslational modification of this protein with pancreatic canine microsomes yields the expected M(r) 100,000 PSM antigen. Following transfection of PC-3 cells with the full-length PSM cDNA in a eukaryotic expression vector, we detect expression of the PSM glycoprotein by Western analysis using the 7E11-C5.3 monoclonal antibody. Ribonuclease protection analysis demonstrates that the expression of PSM mRNA is almost entirely prostate specific in human tissues. PSM expression appears to be highest in hormone-deprived states and is hormonally modulated by steroids, with 5-alpha-dihydrotestosterone down-regulating PSM expression in the human prostate cancer cell line LNCaP by 8-10-fold, testosterone down-regulating PSM by 3-4-fold, and corticosteroids showing no significant effect. Normal and malignant prostatic tissues consistently show high PSM expression, whereas we have noted heterogeneous, and at times absent, expression of PSM in benign prostatic hyperplasia. LNCaP tumors implanted and grown both orthotopically and s.c. in nude mice abundantly express PSM, providing an excellent in vivo model system to study the regulation and modulation of PSM expression.
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            Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer

            Martina Weineisen, Jakub Šimeček, Margret Schottelius … (2014)
            Background Due to its high expression in prostate cancer, PSMA (prostate-specific membrane antigen) represents an ideal target for both diagnostic imaging and endoradiotherapeutic approaches. Based on a previously published highly specific PSMA ligand ([68Ga]DOTA-FFK(Sub-KuE)), we developed a corresponding metabolically stable 1,4,7,10-tetraazacyclododececane,1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA) construct for theranostic treatment of prostate cancer. Methods All ligands were synthesized by a combined solid phase and solution phase synthesis strategy. The affinity of the natgallium and lutetium complexes to PSMA and the internalization efficiency of the radiotracers were determined on PSMA-expressing LNCaP cells. The 68Ga- and 177Lu-labelled ligands were further investigated for lipophilicity, binding specificity, metabolic stability, as well as biodistribution and μPET in LNCaP-tumour-bearing mice. Results Radiochemical yields for 68Ga (3 nmol, 5.0 M NaCl/2.7 M HEPES (approximately 5/1), pH 3.5 to 4.5, 5 min, 95°C) and 177Lu labelling (0.7 nmol, 0.1 M NH4OAc, pH 5.5, 30 min, 95°C) were almost quantitative, resulting in specific activities of 250 to 300 GBq/μmol for the 68Ga analogues and 38 GBq/μmol for 177Lu complexes. Due to metabolic instability of l-amino acid spacers, d-amino acids were implemented resulting in a metabolically stable DOTAGA ligand. Compared to the DOTA ligand, the DOTAGA derivatives showed higher hydrophilicity (logP = −3.6 ± 0.1 and −3.9 ± 0.1 for 68Ga and 177Lu, respectively) and improved affinity to PSMA resulting in an about twofold increased specific internalization of the 68Ga- and 177Lu-labelled DOTAGA analogue. Especially, [68Ga]DOTAGA-ffk(Sub-KuE) exhibits favourable pharmacokinetics, low unspecific uptake and high tumour accumulation in LNCaP-tumour-bearing mice. Conclusions The pair of diagnostic/therapeutic PSMA-ligands [68Ga/177Lu]DOTAGA-ffk(Sub-KuE) possess remarkable potential for the management of prostate cancer.
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              68 Ga-Based Radiopharmaceuticals: Production and Application Relationship

              Irina Velikyan (2015)
              The contribution of 68Ga to the promotion and expansion of clinical research and routine positron emission tomography (PET) for earlier better diagnostics and individualized medicine is considerable. The potential applications of 68Ga-comprising imaging agents include targeted, pre-targeted and non-targeted imaging. This review discusses the key aspects of the production of 68Ga and 68Ga-based radiopharmaceuticals in the light of the impact of regulatory requirements and endpoint pre-clinical and clinical applications.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Turk J Chem
                Journal ID (iso-abbrev): Turk J Chem
                Title: Turkish Journal of Chemistry
                Publisher: The Scientific and Technological Research Council of Turkey
                ISSN (Print): 1300-0527
                ISSN (Electronic): 1303-6130
                Publication date Collection: 2021
                Publication date (Electronic): 17 February 2021
                Volume: 45
                Issue: 1
                Pages: 26-34
                Affiliations
                [1 ] Department of Nuclear Medicine, Pamukkale University, Education and Research Hospital, Denizli Turkey
                [2 ] Department of Biomedical Engineering, Faculty of Technology, Pamukkale University, Denizli Turkey
                [3 ] Department of Nuclear Medicine, Medical Faculty, Pamukkale University, Denizli Turkey
                Author notes
                * To whom correspondence should be addressed. E-mail: ayseugur@ 123456pau.edu.tr

                CONFLICT OF INTEREST:

                none declared

                Author information
                https://orcid.org/0000-0003-0913-6943
                https://orcid.org/0000-0002-6833-6083
                https://orcid.org/0000-0003-0983-2834
                Article
                DOI: 10.3906/kim-2003-19
                PMC ID: 7925295
                PubMed ID: 33679149
                SO-VID: bd048155-6d0e-49f6-8132-fbf931561c67
                Copyright © Copyright © 2021 The Author(s)
                License:

                This article is distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                Date received : 13 March 2020
                Date accepted : 29 September 2020
                Categories
                Subject: Article

                Keywords: imaging agents,radiolabeling,radiochemical purity,radio-hplc,quality control
                Data availability:
                Keywords: imaging agents, radiolabeling, radiochemical purity, radio-hplc, quality control

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