Preclinical testing of N-[C-11]-methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate, a novel radioligand for detection of cerebral muscarinic receptors using PET

The muscarinic antagonist N-[C-11]methyl-piperidin-4-yl 2-cyclohexyl-2-hydr oxy-2-phenylacetate (VC-004) 1 was tested for visualization of muscarinic r eceptors in the brain. The active (R)-isomer (pKb = 10.92) was labeled by r eacting [C-11]-CH3I with the secondary amine precursor (40-60% decay-correc ted radiochemical yield, specific activity 13.0-34.3 TBq/mmol, 45 min after end of bombardment). Biodistribution studies were performed in male Wistar rats. Brain uptake of(R)-[C-11]-VC-004 was high, standard uptake values (S UVs) ranging from 1.6 in cerebellum to 3.3 in frontal cortex. In all brain regions, the nonsubtype selective muscarinic antagonist scopolamine (2.5 mg /kg) blocked (R)-[C-11]-VC-004 binding to the same extent (84.6 +/- 3.3%) a s nonlabeled (R)-VC-004 (2.0 mg/kg, 83.2 +/- 4.6%). In contrast, the fracti on of [C-11]VC-004 binding which was blocked by atropine (2.5 mg/kg) was si gnificantly smaller (54 +/- 17%). The reduction of (R)-[C-11]-VC-004 bindin g by low-dose atropine (0.5 mg/kg) was not significantly different from tha t caused by (R)-(-)-QNB (20 mu g/kg). The decrease in specific binding of ( R)-[C-11]VC-004 after (R)-(-)-QNB block correlated well with literature val ues for the percentages of Mt receptors in the brain regions studied. (R)-[ C-11]VC-004 was rapidly cleared from plasma (92% with a half-life of 0.27 m in) and the fraction of total plasma radioactivity representing parent comp ound decreased from 99% to 42% at 10 min postinjection. Although (R)-[C-11] VC-004 can visualize muscarinic receptors in the brain, it does not show se lectivity for the Ma-subtype. A low dose (0.5 mg/kg) of atropine seems to p referentially block M-2-receptors in vivo, as has been reported for (R)-(-) -QNB. Synapse 35:62-67, 2000. (C) 2000 Wiley-Liss, Inc.