title: 123I-labeled AM251: a radioiodinated ligand which binds in vivo to mouse brain cannabinoid CB1 receptors.
abstract: We have investigated the binding of 123I-labeled N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methy l-1 H-pyrazole-3-carboxamide (AM251), an analog of the cannabinoid receptor antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-carboxamide] in the mouse brain. Following intravenous injection, the peak whole-brain uptake of about 1% of the administered activity occurred at about 2 h. By 8 h radioactivity in brain had declined to about half its peak value. High-performance liquid chromatographic analysis showed that > 70% of radioactivity extracted from brain at 2 h was still present as [123I]AM251. Co-injection of SR141716A inhibited the in vivo brain binding of [123I]AM251 dose dependently. At 2 mg/kg, the highest dose that could be tested, inhibition was 50% at 2 h post-administration. The ED50 value calculated assuming that 2 mg/kg gave near-maximal inhibition was about 0.1 mg/kg. In contrast to the brain, radioactivity in other major organs (blood, liver, kidney, heart and lung) was little affected by SR141716A. The regional binding of [123I]AM251 in the brain was consistent with the published distribution of cannabinoid receptors in rat brain, in that the order was hippocampus, striatum > cerebellum > brain stem. delta 9-Tetrahydrocannabinol co-administered intravenously at 10 mg/kg, a dose which induced catalepsy and decreased locomotor activity, decreased the 2 h brain uptake of [123I]AM251 by 10%, but this was not significant (P = 0.08). In in vitro binding assays with mouse hippocampal membranes, tetrahydrocannabinol inhibited binding of [123I]AM251 with an IC50 value of about 700 nM, compared with about 0.2 nM for SR141716A.
authors.affiliation: Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. gatley@brain.med.bnl.gov
authors.forename: S J
authors.initials: SJ
authors.lastname: Gatley
authors.forename: A N
authors.initials: AN
authors.lastname: Gifford
authors.forename: N D
authors.initials: ND
authors.lastname: Volkow
authors.forename: R
authors.initials: R
authors.lastname: Lan
authors.forename: A
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D013759:Dronabinol / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D000077285:Rimonabant; D014018:Tissue Distribution
chemical_list: D007457:Iodine Radioisotopes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C103505:AM 251; D013759:Dronabinol; D000077285:Rimonabant