title: 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.
abstract: 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.
authors.affiliation: Positron Emission Tomography (PET) Center, Groningen University Hospital, Groningen, The Netherlands.
authors.forename: T J
authors.initials: TJ
authors.lastname: Visser
authors.forename: A
authors.initials: A
authors.lastname: Van Waarde
authors.forename: P
authors.initials: P
authors.lastname: Doze
authors.forename: T
authors.initials: T
authors.lastname: Wegman
authors.forename: W
authors.initials: W
authors.lastname: Vaalburg
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010648:Phenylacetates / Q000493:pharmacokinetics*; D011813:Quinuclidinyl Benzilate / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000378:metabolism*; D014055:Tomography, Emission-Computed
chemical_list: D018727:Muscarinic Antagonists; D010648:Phenylacetates; D011976:Receptors, Muscarinic; C003489:N-methylpiperidine-4-yl-2-cyclohexyl-2-hydroxy-2- phenylacetate; D011813:Quinuclidinyl Benzilate