Design, Evaluation, and Comparison of Ghrelin Receptor Agonists and Inverse Agonists as Suitable Radiotracers for PET Imaging

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• 作者：Constance Chollet ; Ralf Bergmann ; Jens Pietzsch ; Annette G. Beck-Sickinger
• 刊名：Bioconjugate Chemistry
• 出版年：2012
• 出版时间：April 18, 2012
• 年：2012
• 卷：23
• 期：4
• 页码：771-784
• 全文大小：648K
• 年卷期：v.23,no.4(April 18, 2012)
• ISSN：1520-4812

文摘

Ghrelin agonist and inverse agonist radiotracers, suitable for positron emission tomography (PET), were developed to study the behavior of ghrelin receptor ligands in vivo and for further design of druggable peptides. The target peptides were synthesized on solid support and conjugated to the bifunctional chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), which is known to form a stable complex with Ga³⁺. Complexation with ⁶⁸Ga could be achieved under mild conditions and led to radiotracers with high radiochemical purity and specific activity. The biological activity of the radiotracers was evaluated in vitro by an inositol phosphate turnover assay. Pharmacokinetic profile and metabolic stability of the ⁶⁸Ga-NODAGA-radiotracers were investigated by small animal PET in rodent. Ghrelin derived agonists presented very high kidney accumulation, negligible tissue distribution, fast blood clearance, and poor stability in blood. Contrarily, the inverse agonist radiotracer exhibited very high stability in blood, large diffusion in tissues, reasonable kidney and liver metabolism, and slow blood clearance. This pharmacokinetic profile makes the ghrelin inverse agonist motif KwFwLL-CONH₂ suitable for further development of radiotracers and a promising lead to design peptide-based therapeutics against obesity.