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AAPS PharmSci. 1999;1(2):E4.

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

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Department of Pharmaceutical Sciences and Molecular and Cell Biology, U-92, University of Connecticut, Storrs, CT 06269, USA.


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 K(i) 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.

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