Radiosynthesis and in vivo evaluation of a F-18-labeled pancreatic islet amyloid inhibitor

摘要

Formation of islet amyloid deposits contributes to the progressive loss of beta-cells in Type 2 diabetes. Islet amyloid is composed of islet amyloid polypeptide (IAPP). [(N-Me)G24, (N-Me)I26]hIAPP(22-27) peptide was found to bind human IAPP with high-affinity and inhibit fibrillogenesis. We labeled [(N-Me)G24, (N-Me)I26] hIAPP(22-27) with fluorine-18 using N-succinimidyl-4-[18F] fluorobenzoate. Results from biodistribution studies in healthy CF-1 mice at 1 h p.i. indicated that 18F-peptide was cleared efficiently (0.04±0.02%ID/g remained in blood). The primary route of clearance from the body appears to be hepatobiliary. Radioactivity accumulation in liver, intestine, and kidney was 6.7±2.9, 60.3±18.5, and 0.2±0.0%ID, respectively. Other organs accumulated negligible radioactivity. As normal mice do not develop pancreatic amyloid deposits, only background radioactivity was seen in pancreas. The radio-HPLC analysis of mouse urine at 2 h p.i. showed that ～29.3% of injected 18F-peptide excreted intact along with two additional metabolite peaks. Dynamic microPET/CT imaging of a CF-1 mouse injected with 18F-peptide indicated that radiotracer was rapidly taken up by liver and most of it moved into intestine within 10 min. The results provide a useful insight into the biological disposition of [(N-Me)G24, (N-Me)I26]hIAPP(22-27) that is being developed as a pancreatic amyloid inhibitor.