Evaluation of deuterated [(18)F]JHU94620 for imaging cannabinoid type 2 receptors in rodent and monkey brain.

PET imaging of cannabinoid type-2 receptors (CB2Rs) in the healthy brain remains challenging due to low receptor density and the unavailability of radiotracers with high affinity and selectivity. Because some carbon-deuterium bonds are less susceptible than carbon-proton bonds to enzymatic cleavage, deuteration of [(18)F]JHU94620 was pursued to potentially slow its metabolism. This study: (1) evaluated the sensitivity of a heavily deuterated version of the agonist [(18)F]JHU94620 ([(18)F]JHU94620-d(8)) to detect brain CB2Rs in healthy Sprague-Dawley rats and monkeys and in a rat model of inflammation; (2) assessed the metabolic stability of [(18)F]JHU94620 and [(18)F]JHU94620-d(8) in whole blood, plasma, and brain of control (FVB) mice and in the whole blood and plasma of monkeys; and (3) investigated the efflux transporter substrate liability of [(18)F]JHU94620-d(8). Deuteration of [(18)F]JHU94620 did not significantly affect its uptake in the brains of FVB mice, Sprague-Dawley rats, or monkeys, nor did it affect metabolic stability, except in FVB mice. [(18)F]JHU94620-d(8) was also found to be a moderate substrate for efflux transporters in monkeys but not in mice. The sensitivity of [(18)F]JHU94620-d(8) was inadequate to detect the low density of CB2Rs that are in the agonist-preferring state in the brain.