Kinetic modeling of Fatty Acid Amide Hydrolase (FAAH) enzyme occupancy after JNJ-42165279 inhibition based on 11C-MK-3168 PET imaging of human brain.

362 Objectives FAAH catalyzes the degradation of fatty acid amides (FAA), including endocannabinoids that act as endogenous agonists of cannabinoid receptors. Preclinical data suggest that modulation of FAAH may have therapeutic benefits in anxiety, mood, and stress disorders. MK-3168 and JNJ-42165279 are both reversible inhibitors of FAAH, acting as a substrate and covalently binding to the catalytic site. 11C-MK-3168 PET imaging was applied to determine the optimal dose for FAAH inhibition in brain. Methods The regional brain kinetics of 11C-MK-3168 and blocking of the retention of the radioligand by JNJ-42165279 was tested in an open-label, adaptive dose design. 11C-MK-3168 PET scans were conducted at baseline and after doses of JNJ-42165279 ranging from 2.5 to 50 mg after single dose and at steady state. The pharmacokinetic model was optimized to measure dose dependent reduction in enzyme occupancy by 11C-MK-3168. Results A two-tissue (2T) reversible model with non-displaceable distribution volume fixed for total grey matter at the blocked condition was used for quantification with changes in binding potential as indicator for FAAH occupancy. JNJ-42165279 slowed 11C-MK-3168 metabolism in a dose-dependent manner. Single doses as low as 10 mg resulted in >95% occupancy. One week dosing of JNJ42165279 with 2.5 and 10 mg was associated with sustained occupancy at trough levels, but with no evidence of accumulation. Conclusions A 2T reversible quantification method using binding potential, developed for blocking studies with the high affinity FAAH compound 11C-MK-3168 extended the potential range of centrally active doses of JNJ-42165279 .