Preclinical testing of N-[11c]-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.

27 Radiochemistry

“…Since [ 11 C]methyl iodide can be made rapidly and is a most versatile reagent, it is widely used in the synthesis of more complex labelled molecules. Recent examples have been in the preparation of dechloroepibatidine, 60 substituted methylenedioxyamphetamines, 61 ()N-methyl-3-piperidyl benzilate, 62 caffeine derivatives, 63 tropane derivatives 64 and N-methylpiperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate, 65 all labelled with 11 C in a methyl group. The labelled methyl iodide can either be made from the reaction of [ 11 C]methane with iodine 64 or by the reaction of [ 11 C]carbon dioxide with a methyl Grignard reagent followed by reduction with lithium aluminium hydride and reaction with hydrogen iodide.…”

Pulmonary PET imaging confirms preferential lung target occupancy of an inhaled bronchodilator

“…For that purpose, we selected the reference drug ipratropium, an antagonist at muscarinic acetylcholine receptors, and studied its binding to lungs and the pituitary gland in non-human primates. To estimate ipratropium-induced muscarinic receptor occupancy, we used the previously developed radioligand, 11 C-VC-002, that had been successfully applied in the study of muscarinic receptors in the human airways [6, 7]. To the best of our knowledge, this represents the first study that addresses the relationships between the route of administration, plasma drug concentration, and drug-induced receptor occupancy in vivo in pulmonary tissue.…”