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. 1999 Jun 20;1(2):39–45. doi: 10.1208/ps010204

Design and synthesis of the CB1 selective cannabinoid antagonist AM281: A potential human SPECT ligand

Ruoxi Lan 1,✉, Qian Lu 1, Pusheng Fan 1, John Gatley 2, Nora D Volkow 2, Susanthi R Fernando 3, Roger Pertwee 3, Alexandros Makriyannis 1,4,✉
PMCID: PMC2761119  PMID: 11741201

Abstract

In the search for a radioligand capable of imaging cannabinoid CB1 receptors in the living human brain by SPECT (single photon emission computed tomography), N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) was synthesized. This compound is an analog of the potent, CB1 receptor selective antagonist SR141716A [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide]. AM281 bound to brain and spleen membrane preparations (CB1 and CB2 receptors, respectively) with Ki values of 12 nM and 4200 nM, respectively. AM281 also inhibited the response of guinea-pig small intestine preparation to a cannabinoid receptor agonist. Thus, AM281 behaves as a CB1 receptor selective antagonist. Methods for the rapid, high-yield synthesis and purification of [123I]AM281 were developed, and transaxially reconstructed brain SPECT images obtained after continuous infusion of [123I]AM281 in baboons. Thus [123I]AM281 may be suitable for imaging CB1 receptors in humans.

Key Words: AM281, cannabinoid CB1 receptor, cannabinoid receptor antagonist, CB1 selective ligand, SPECT image

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