Translational studies with [11C]MK-3168, a PET tracer for fatty acid amide hydrolase (FAAH)

397 Objectives [11C]MK-3168 is a novel PET tracer for fatty acid amide hydrolase (FAAH). Inhibition of FAAH, an enzyme causing anandamide degradation, results in analgesia and anti-inflammatory effects in animal models. FAAH is expressed in the central and peripheral nervous systems. Central inhibition is needed for maximal analgesic efficacy. A FAAH PET tracer would enable confirmation of sufficient central target engagement and assist dose selection for clinical proof-of-concept studies. Using [11C]MK-3168, drug plasma level versus occupancy relationship for a selective FAAH inhibitor (FI) was determined in rhesus monkey. First-in-human scans were also performed to test the tracer9s utility in human. Methods Rhesus monkey: Initial [11C]MK-3168 studies (baseline and blocking scans) were performed with arterial input function (AIF) measurement . These studies determined the presence of a reference region and estimated the non-displaceable binding potential (BPND). After selecting an appropriate quantification method, blocking scans post-FI dosing were performed to obtain the drug plasma level versus occupancy relationship. Human: First-in-human scans included test-retest (TRT) scans with AIF measurement and whole body scans to measure the effective radiation dose. Results [11C]MK-3168 TACs in rhesus and human were modeled satisfactorily with a 2 tissue compartment model. Rhesus monkey: BPND between 0.4 and 1 and volume of distribution (VT) between 3 and 4 were estimated for thalamus, cortex, cerebellum and striatum. White matter VT changed little between baseline and blocking scans ( Conclusions [11C]MK-3168 is a promising PET tracer for measuring FAAH availability and occupancy in rhesus monkey and human