Radiosynthesis and in vivo evaluation of a F-18-labeled pancreatic islet amyloid inhibitor Gopal Pathuri, Hrushikesh B. Agashe, Vibhudutta Awasthi, and Hariprasad Gali à 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)G 24 , (N-Me)I 26 ]hIAPP(22–27) peptide was found to bind human IAPP with high-affinity and inhibit fibrillogenesis. We labeled [(N-Me)G 24 , (N-Me)I 26 ]hIAPP(22–27) with fluorine-18 using N-succinimidyl-4-[ 18 F]fluorobenzoate. Results from biodistribution studies in healthy CF-1 mice at 1 h p.i. indicated that 18 F-peptide was cleared efficiently (0.0470.02%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 6.772.9, 60.3718.5, and 0.270.0%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 18 F-peptide excreted intact along with two additional metabolite peaks. Dynamic microPET/CT imaging of a CF-1 mouse injected with 18 F-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)G 24 , (N-Me)I 26 ]hIAPP(22–27) that is being developed as a pancreatic amyloid inhibitor. Keywords: pancreatic islet amyloid; hIAPP(22–27); inhibitor; [ 18 F]SFB; [ 18 F]FBA; PET imaging; F-18-labeled peptide; biodistribution; pharmacokinetics; metabolic stability Introduction Several studies suggest that the formation of pancreatic islet amyloid deposits may be a major contributor to the progressive loss of pancreatic beta-cells. 1–4 These deposits are known to be a characteristic pathologic feature of the pancreas in 490% of patients with Type 2 diabetes. 5–6 Pancreatic islet amyloid deposits in humans consist mainly of b sheet fibrillar aggregates of the 37-amino acid islet amyloid polypeptide (IAPP or amylin). 4,5,7 IAPP is a neuroendocrine hormone of the calcitonin family of polypeptide hormones, and is produced and co- secreted with insulin in response to beta-cell stimulation by both glucose and non-glucose secretagogues. 8 IAPP is over- produced in states of insulin resistance, a typical feature of Type 2 diabetes. Excess IAPP promotes self-aggregation and amyloid fibril formation that are thought to be toxic to beta-cells. 4 That islet amyloidosis is an early factor responsible for beta-cell failure is strongly supported by the in vitro cytotoxic effect of human islet amyloid polypeptide (hIAPP), as well as by the results from in vivo hIAPP transgenic mouse studies. 9,10 The precise mechanisms by which hIAPP-derived fibrils induce beta-cell death and dysfunction are still not clear. It has been suggested that the presence of hIAPP fibrils between islet cells and capillary endothelial cells may impair movement of nutrients (such as glucose) from the bloodstream into beta-cells. At the same time, insulin exocytosed by beta-cells also faces this barrier before reaching the circulation. 11,12 Another proposed mechanism is that these fibrils form pores in the membrane that allows extracellular calcium to enter the cell resulting in apoptotic cell death. 13,14 However, recently it has been suggested that prefibrillar aggregates (or oligomers) formed early during aggregation, and not mature amyloid fibrils, are the cytotoxic species in Type 2 diabetes. 15,16 Although the sequence of IAPP is strongly conserved over a number of animal species, IAPP-derived amyloid is only formed by humans, cats, and few non-human primates. 17 Rodents do not form pancreatic amyloid, although rat IAPP sequence differs from its human analog by only six amino acid residues. Considering that five of these six amino acid residues are located between residues 20 and 29, amyloidogenicity of hIAPP has been related to these residues. It has been shown that the synthetic decapeptide hIAPP(20–29) is able to form fibrils with morphology that is similar to the fibrils formed by the complete hIAPP sequence. 18 The ‘amyloid core’ has been further narrowed down to the residues 22–27 (NFGAIL) that has been shown to 186 Small Animal Imaging Facility, Department of Pharmaceutical Sciences, The University of Oklahoma College of Pharmacy, Oklahoma City, OK 73117, USA *Correspondence to: Hariprasad Gali, The University of Oklahoma College of Pharmacy, 1110 N. Stonewall Avenue, Room 301, Oklahoma City, OK 73117, USA. E-mail: hgali@ouhsc.edu Research Article Received 18 December 2009, Revised 20 January 2010, Accepted 25 January 2010 Published online 30 March 2010 in Wiley Interscience (www.interscience.wiley.com) DOI: 10.1002/jlcr.1748 J. Label Compd. Radiopharm 2010, 53 186–191 Copyright r 2010 John Wiley & Sons, Ltd.