title: Design and synthesis of the CB1 selective cannabinoid antagonist AM281: a potential human SPECT ligand.
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 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.
authors.affiliation: Department of Pharmaceutical Sciences and Molecular and Cell Biology, U-92, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: R
authors.initials: R
authors.lastname: Lan
authors.forename: J
authors.initials: J
authors.lastname: Gatley
authors.forename: Q
authors.initials: Q
authors.lastname: Lu
authors.forename: P
authors.initials: P
authors.lastname: Fan
authors.forename: S R
authors.initials: SR
authors.lastname: Fernando
authors.forename: N D
authors.initials: ND
authors.lastname: Volkow
authors.forename: R
authors.initials: R
authors.lastname: Pertwee
authors.forename: A
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002186:Cannabinoids / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000187:drug effects / Q000502:physiology; D007457:Iodine Radioisotopes; D008024:Ligands; D051379:Mice; D009025:Morpholines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010215:Papio; D016548:Prosencephalon / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D002186:Cannabinoids; C469526:Cnr2 protein, rat; D007457:Iodine Radioisotopes; D008024:Ligands; D009025:Morpholines; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C109925:AM 281