Preclinical testing of N-[(11)c]-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-[(11)C]methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate (VC-004) 1 was tested for visualization of muscarinic receptors in the brain. The active (R)-isomer (pKb = 10.92) was labeled by reacting [(11)C]-CH(3)I with the secondary amine precursor (40-60% decay-corrected 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)-[(11)C]-VC-004 was high, standard uptake values (SUVs) 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)-[(11)C]-VC-004 binding to the same extent (84.6 +/- 3.3%) as nonlabeled (R)-VC-004 (2.0 mg/kg, 83.2 +/- 4.6%). In contrast, the fraction of [(11)C]VC-004 binding which was blocked by atropine (2.5 mg/kg) was significantly smaller (54 +/- 17%). The reduction of (R)-[(11)C]-VC-004 binding by low-dose atropine (0.5 mg/kg) was not significantly different from that caused by (R)-(-)-QNB (20 microg/kg). The decrease in specific binding of (R)-[(11)C]VC-004 after (R)-(-)-QNB block correlated well with literature values for the percentages of M(2) receptors in the brain regions studied. (R)-[(11)C]VC-004 was rapidly cleared from plasma (92% with a half-life of 0.27 min) and the fraction of total plasma radioactivity representing parent compound decreased from 99% to 42% at 10 min postinjection. Although (R)-[(11)C]VC-004 can visualize muscarinic receptors in the brain, it does not show selectivity for the M(2)-subtype. A low dose (0.5 mg/kg) of atropine seems to preferentially block M(2)-receptors in vivo, as has been reported for (R)-(-)-QNB. Copyright 2000 Wiley-Liss, Inc.