Synthesis and evaluation of [18F]exendin (9–39) as a potential biomarker to measure pancreatic β-cell mass

Abstract

Glucagon-like peptide 1 (GLP-1) is released in response to food intake and plays an important role in maintaining blood glucose homeostasis. Exendin (9-39), a potent glucagon-like peptide 1 receptor antagonist, has been labeled with In-111 for SPECT imaging. We report here the first radiosynthesis of [(18)F]exendin (9-39) ([(18)F]Ex(9-39)) and an evaluation of its potential as a biomarker for in vivo positron emission tomography (PET) imaging of pancreatic β-cell mass (BCM) in rats. F-18 label was introduced by conjugation of [(18)F]4-fluorobenzaldehyde with an Ex(9-39) derivative containing a 6-hydrazinonicotinyl group on the ε-amine of Lys27. Positron emission tomography imaging was carried out in Sprague-Dawley rats (five control and five streptozotocin-induced diabetic) and BioBreeding diabetes-prone rats (three at 7 weeks and three at 12 weeks) using the high-resolution research tomograph (HRRT) after 0.187 ± 0.084 mCi [(18)F]Ex(9-39) administration. Time-activity curves were obtained from pancreas, liver and kidney. Pancreases were assayed for insulin content after the imaging study. Site-specifically labeled [(18)F]Ex(9-39) was purified on a G15 open column with radiochemical and chemical purities >98%. Positron emission tomography imaging showed pancreatic standardized uptake value (SUV) peaked at 10 min and plateaued by 50 min to the end of scan (240 min). No correlations of pancreatic SUV with postmortem measures of insulin content were seen. [(18)F]Ex(9-39) was successfully prepared and used for PET imaging for the first time to measure pancreatic BCM. The results suggest that derivatization of the Lys27 residue might reduce binding affinity, as evidenced by the absence of specific binding. Exendin analogues radiolabeled at other sites may elucidate the active site required for binding.