Development and <i>in vivo</i> evaluation of a novel kappa opioid receptor agonist as PET radiotracer with superior imaging characteristics

摘要： Studies have shown kappa opioid receptor (KOR) abnormalities in addictive disorders, other central nervous system diseases and Alzheimer’s disease. We have developed the first set of agonist 11C-GR103545 and antagonist 11C-LY2795050 radiotracers for positron emission tomography imaging of KOR in human. Nonetheless, 11C-GR103545 displays protracted uptake kinetics and is not an optimal radiotracer. Here we report the development and evaluation of 11C-EKAP and its comparison with 11C-GR103545. Methods: EKAP was synthesized and assayed for in vitro binding affinities, then radiolabeled with 11C-CH3OTf. PET studies were carried out in rhesus monkeys. Blocking studies were performed with naloxone and the selective KOR antagonists LY2795050 and LY2456302. Arterial input functions were generated for use in kinetic modeling. Brain time-activity curves were analyzed with the multilinear analysis 1 (MA1) method to derive binding parameters. Results: EKAP has high KOR affinity (Ki = 0.28 nM) and good selectivity in vitro. 11C-EKAP was prepared in good radiochemical purity. 11C-EKAP rapidly metabolized in plasma, and displayed fast and reversible kinetics in brain 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 11C-EKAP specific binding, thus demonstrating its binding specificity and selectivity in vivo. Mean MA1-derived BPND values were 1.74, 1.79, 1.46, 0.80 and 0.77 for cingulate cortex, globus pallidus, insula, striatum and frontal cortex, consistent with the known KOR distribution in primate brains. Conclusions: We have successfully developed 11C-EKAP as a novel KOR agonist tracer with dual attractive imaging properties of fast uptake kinetics and high specific binding in vivo.