Synthesis and biodistribution of [¹¹C]R116301, a promising PET ligand for central NK₁ receptors

N1-(2,6-Dimethylphenyl)-2-(4-{(2R,4S)-2-benzyl-1-[3,5-di(trifluoromethyl) [carbonyl-¹¹C]benzoyl]hexahydro-4-pyridinyl}piperazino)acetamide ([¹¹C]R116301) was prepared and evaluated as a potential positron emission tomography (PET) ligand for investigation of central neurokinin(1) (NK₁) receptors. 1-Bromo-3,5-di(trifluoromethyl)benzene was converted in three steps into 3,5-di(trifluoromethyl)[carbonyl-¹¹C]benzoyl chloride, which was reacted with N1-(2,6-dimethylphenyl)-2-{4-[(2R,4S)-2- benzylhexahydro-4-pyridinyl]piperazino}acetamide providing [¹¹C] R116301 in 45-57% decay-corrected radiochemical yield. The total synthesis time, from end of bombardment (EOB) to the formulated product, was 35 min. Specific activity (SA) was 82-172 GBq/μmol (n = 10) at the end of synthesis. N1-([4-³H]-2,6-Dimethylphenyl)-2-(4-{(2R,4S)-2-benzyl-1-[3,5- di(trifluoromethyl)benzoyl]hexahydro-4-pyridinyl}piperazino)acetamide ([ ³H]R116301) was also synthesized (SA: 467 GBq/mmol). The B _max for [³H]R116301 measured in vitro on Chinese hamster ovary cell membranes stably transfected with the human NK₁ receptor was 19.10 ± 1.02 pmol/mg protein with an apparent dissociation constant of 0.08 ± 0.01 nM. Ex vivo, in vivo and in vitro autoradiography studies with [³H]R116301 in gerbils demonstrated a preferential accumulation of the radioactivity in the striatum, olfactory tubercule, olfactory bulb and locus coeruleus. In vivo, the biodistribution of [¹¹C]R116301 in gerbils revealed that the highest initial uptake is in the lung, followed by the liver and kidney. In the brain, maximum accumulation was found in the olfactory tubercules (1.10 ± 0.08 injected dose (ID)/g 20 min post injection (p.i.)) and the nucleus accumbens (1.00 ± 0.12 ID/g 10 min p.i.). Tissue/cerebellum concentration ratios for striatum and nucleus accumbens increased with time due to rapid uptake followed by a slow wash out (1.29 and 1.64, respectively, 30 min p.i.). A tissue to cerebellum ratio of 1.33 and 1.62 was also observed for olfactory bulb and olfactory tubercules, respectively (20 min p.i.). In summary, [¹¹C]R116301 appears to be a promising radioligand suitable for the visualization of NK₁ receptors in vivo using PET.