Novel kappa opioid receptor agonist as improved PET radiotracer: Development and in vivo evaluation.

The kappa opioid receptor (KOR) is involved in depression, alcoholism and drug abuse. The current agonist radiotracer 11 C-GR103545 is not ideal for imaging KOR due to its slow tissue kinetics in human. The aim of our project was to develop novel KOR agonist radiotracers with improved imaging properties. A novel compound FEKAP (( R)-4-(2-(3,4-dichlorophenyl)acetyl)-3-((ethyl(2-fluoroethyl)amino)methyl) piperazine-1-carboxylate) was designed, synthesized and assayed for in vitro binding affinities. It was then radiolabeled and evaluated in rhesus monkeys. Baseline and blocking scans were conducted on a Focus-220 scanner to assess binding specificity and selectivity. Metabolite-corrected arterial activities over time were measured and used as input functions to analyze the brain regional time-activity curves and derive kinetic and binding parameters with kinetic modeling. FEKAP displayed high KOR binding affinity ( Ki = 0.43 nM) and selectivity (17 folds over mu opioid receptor and 323 folds over delta opioid receptor) in vitro. 11 C-FEKAP was prepared in high molar activity (mean of 718 GBq/μmol, n = 19) and > 99% radiochemical purity. In monkeys 11 C-FEKAP metabolized fairly fast, with ~31% of parent fraction at 30 min post-injection. In the brain it exhibited fast and reversible kinetics with good uptake. Pre-treatment with the non-selective opioid receptor antagonist naloxone (1 mg/kg) decreased uptake in high binding regions to the level in the cerebellum, and the selective KOR antagonist LY2456302 (0.02 & 0.1 mg/kg) reduced 11 C-FEKAP specific binding in a dose-dependent manner. As a measure of specific binding signals, the mean binding potential (BPND) values of 11 C-FEKAP derived from the multilinear analysis-1 (MA1) method were great than 0.5 for all regions except for the thalamus. The novel KOR agonist tracer 11 C-FEKAP demonstrated binding specificity and selectivity in vivo and exhibited attractive properties of fast tissue kinetics and high specific binding.