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 μg/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. Synapse 35:62–67, 2000. © 2000 Wiley‐Liss, Inc.