Irina Velikyan1, Ulrika Rosenström2, Sergio Estrada2, Ingrid Ljungvall3, Jens Häggström3, Olof Eriksson2, Gunnar Antoni4. 1. Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, SE-75183 Uppsala, Sweden. Electronic address: irina.velikyan@bms.uu.se. 2. Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, SE-75183 Uppsala, Sweden. 3. Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden. 4. Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, SE-75183 Uppsala, Sweden. Electronic address: gunnar.antoni@akademiska.se.
Abstract
OBJECTIVES: Fibrosis 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. METHODS: A 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 (68)Ga. 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. RESULTS: The 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 [[(68)Ga]Ga-NOTA](+1)-PEG2-c[CPGRVMHGLHLGDDEGPC] as compared to [[(68)Ga]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 [(68)Ga]Ga-NO2A-Col and [(68)Ga]Ga-NODAGA-Col. CONCLUSIONS: Two 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.
OBJECTIVES:Fibrosis 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. METHODS: A 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 (68)Ga. 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. RESULTS: The 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 [[(68)Ga]Ga-NOTA](+1)-PEG2-c[CPGRVMHGLHLGDDEGPC] as compared to [[(68)Ga]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 [(68)Ga]Ga-NO2A-Col and [(68)Ga]Ga-NODAGA-Col. CONCLUSIONS: Two 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.
Authors: Heejung Kim; Sung-Jin Lee; Jin Su Kim; Cynthia Davies-Venn; Hong-Jun Cho; Samuel J Won; Eden Dejene; Zhengsheng Yao; Insook Kim; Chang H Paik; David A Bluemke Journal: Nucl Med Commun Date: 2016-12 Impact factor: 1.690
Authors: Giuseppe Floresta; George P Keeling; Siham Memdouh; Levente K Meszaros; Rafael T M de Rosales; Vincenzo Abbate Journal: Biomedicines Date: 2021-04-01