Development and in vivo evaluation of a novel kappa opioid receptor agonist as PET radiotracer with superior imaging characteristics.

Studies have shown kappa opioid receptor (KOR) abnormalities in addictive disorders and other central nervous system diseases and Alzheimer's disease. We have developed the first set of agonist 11 C-GR103545 and antagonist 11 C-LY2795050 radiotracers for positron emission tomography imaging of KOR in human. Nonetheless, 11 C-GR103545 displays protracted uptake kinetics and is not an optimal radiotracer. Here we report the development and evaluation of 11 C-EKAP and its comparison with 11 C-GR103545. Methods: EKAP was synthesized and assayed for in vitro binding affinities, then radiolabeled with 11 C-CH3 OTf. PET studies were carried out in rhesus monkeys. Blocking studies were performed with naloxone and selective KOR antagonists (LY2795050 and LY2456302). Arterial input functions were generated. Brain time-activity curves were analyzed with the multilinear analysis 1 (MA1) method to derive binding parameters. Results: EKAP has high KOR affinity ( K i = 0.28 nM) and excellent selectivity in vitro 11 C-EKAP was prepared in good radiochemical purity ( n = 10). 11 C-EKAP rapidly metabolized. It displayed fast and reversible kinetics with peak uptake at <20 min post-injection. Pre-blocking with naloxone (1 mg/kg) or LY2795050 (0.2 mg/kg) produced 84-89% receptor occupancy, while LY2456302 (0.05 & 0.3 mg/kg) dose-dependently reduced 11 C-EKAP specific binding, thus demonstrating its binding specificity and selectivity in vivo Mean MA1-derived BP ND values were 1.74, 1.79, 1.46, 0.80 and 0.77 for cingulate cortex, globus pallidus, insula, striatum and frontal cortex ( n = 5), consistent with the known KOR distribution in primate brains. Conclusion: We have successfully developed 11 C-EKAP as a novel KOR agonist tracer with dual attractive imaging properties of fast uptake kinetics and high specific binding in vivo .