Synthesis and preclinical evaluation of 68Ga-labeled collagelin analogs for imaging and quantification of fibrosis |
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| Affiliation: | 1. Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, SE-75183 Uppsala, Sweden;2. Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden;1. College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA;2. Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA;3. Department of Dermatology, University of New Mexico, Albuquerque, NM 87131, USA;1. CHU de Bordeaux, Service de Médecine Nucléaire, F-33604 Pessac, France;2. Université de Bordeaux 2, Centre de Recherche Cardio-Thoracique, F-33076 Bordeaux, France;3. INSERM U 1045, Centre de Recherche Cardio-Thoracique, F-33076 Bordeaux, France;1. Department of Nuclear Medicine, China-Japan Friendship Hospital, Beijing, 100029, China;2. School of Health Sciences, Purdue University, IN 47907, USA;1. Department of Medical Oncology, Institut Bergonié, Bordeaux;2. Department of Medical Oncology, Clinique Francheville, Périgueux;3. Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif;4. Department of Radiotherapy, Institut Bergonié, Bordeaux, France |
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| Abstract: | ObjectivesFibrosis affecting functionality of vital organs such as liver, lung, heart, and kidney, is involved in many chronic diseases. Positron emission tomography (PET) would not only provide precise localization and extent of the affected tissue but also allow the accurate quantification of the fibrotic process for the subsequent prognosis.MethodsA cyclic peptide c[CPGRVMHGLHLGDDEGPC] conjugated either to 2-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazonan-1-yl)acetic acid (NOTA(tBu)2) or 4-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazacyclononan-1-yl)-5-(tert-butoxy)-5-oxopentanoic acid (NODAGA(tBu)3) via polyethylene glycol link (PEG2) was synthesized and labeled with 68Ga. Non-specific organ distribution, blood clearance, and excretion were investigated ex vivo in healthy rats. The binding specificity of the radioligands was assessed in vitro using autoradiography on cryosections of dog fibrotic heart tissue.ResultsThe yield of NOTA-PEG2-c[CPGRVMHGLHLGDDEGPC] and NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] was 56% and 41%, respectively. Non-decay-corrected radiochemical yield was 80 ± 5% with radiochemical purity of 95 ± 4%. Pharmacokinetic studies in healthy male Sprague–Dawley rats showed fast blood clearance and renal excretion. Lower uptake in liver, spleen, and kidney was found for [[68Ga]Ga-NOTA]+ 1-PEG2-c[CPGRVMHGLHLGDDEGPC] as compared to [[68Ga]Ga-NODAGA]0-PEG2-c[CPGRVMHGLHLGDDEGPC]. Histologic evaluation of the left ventricle (LV) myocardium from a dog with severe mitral regurgitation (MR), revealed mild to moderate perivascular and subendocardial, and mild diffuse interstitial fibrosis. The tracer binding to the cryosections of the tissue was specific with the equilibrium Kd of 2.3 ± 0.8 μM and 2.1 ± 0.9 μM, respectively for [68Ga]Ga-NO2A-Col and [68Ga]Ga-NODAGA-Col.ConclusionsTwo novel peptide based agents for the imaging of fibrosis by PET were developed. Moderation of the biodistribution could be achieved by variation of the charge on the complex moiety of the agents. The combination of the fast clearance from non-target organs as well as organs of interest such as lung, heart, and liver and binding specificity to the target tissue suggests the potential of the analogs for the imaging of fibrosis. |
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