4-(3-((5-(2-[18F]Fluoroethoxy)pyridine-2-yl)oxy)benzylidene)- N-(pyridazin-3-yl)piperidine-1-carboxamide

Excerpt

Fatty acid amide hydrolase (FAAH) is an integral membrane-bound serine hydrolase and a part of the endocannabinoid system (ECS), which comprises the cannabinoid receptors (CB1 and CB2), endogenous ligands termed endocannabinoids (anandamide and oleamide), transporters, and enzymes (1, 2). FAAH plays a key role in the hydrolysis of a number of primary and secondary fatty acid amides, controlling the levels of the neuromodulatory endocannabinoids in the ECS (3, 4). FAAH is widely expressed in many tissues, with the highest levels in the liver and brain (5). Genetic or pharmacological inactivation of FAAH in the brain leads to analgesic, anti-inflammatory, anxiolytic, and anti-depression effects in animal models (6-8).

Cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597) is an irreversible, substrate-like inhibitor of FAAH involving carbamylation of the catalytic nucleophilic Ser²⁴¹ and the O-biaryl group as the leaving group (9-11). On the basis of the structure of URB597, Wyffels et al. (11) prepared biphenyl-3-yl-4-[¹¹C]methoxyphenylcarbamate ([¹¹C]-1) for in vivo positron emission tomography (PET) imaging studies of the brain FAAH in mice. It was proposed that the carbamylation of Ser²⁴¹ would leave the [¹¹C]-methoxyanilino group bound to the FAAH for visualization of FAAH in the brain. However, the results of in vitro and ex vivo studies indicated that [¹¹C]-1 is a reversible inhibitor of FAAH, and the rapid brain washout of the tracer limits its utility as a PET agent for in vivo measurements of FAAH. Wilson et al. (10) reported the ¹¹C-radiolabeling of a close analog of URB597, 6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate (URB694), yielding [¹¹C-carbonyl]URB694 ([¹¹C]CURB) for PET imaging of FAAH in the brain. [¹¹C]CURB showed good brain accumulation with regional heterogeneity, irreversibility, and specific binding to FAAH in vivo in rats.

Skaddan et al. (9) prepared 4-(3-((5-(2-[¹⁸F]fluoroethoxy)pyridine-2-yl)oxy)benzylidene)-N-(pyridazin-3-yl)piperidine-1-carboxamide ([¹⁸F]PF-9811) for use with in vivo PET imaging of FAAH. PF-9811 is a close analog of 4-(3-((5-(2-trifluoromethyl)pyridine-2-yl)oxy)benzylidene)-N-(pyridazin-3-yl)piperidine-1-carboxamide (PF-04457845), which is a clinical candidate for treatment of inflammatory and non-inflammatory pain. [¹⁸F]PF-9811 showed good brain accumulation, with regional heterogeneity and specific binding to FAAH in vivo in rats.