title: Synthesis and structure-activity relationship of a novel series of aminoalkylindoles with potential for imaging the neuronal cannabinoid receptor by positron emission tomography.
abstract: A new series of CB(1) ligands with high binding affinity (K(i) = 0.7-100 nM) and moderate lipophilicity (cLogD(7.4)) in the range of 2.1-4.5 has been synthesized. A structure-activity relationship study demonstrated that for the studied set of aminoalkylindoles, the molecular dipole of the ground state conformation within the series was inversely related to the affinity. The racemic ligand with highest affinity (0.7 nM), 3-(4-fluoronaphthoyl)-1-(N-methylpiperidin-2-ylmethyl)indole, was radiolabeled with (18)F. This radioligand specifically labeled CB(1) receptors in mouse brain and accumulated in regions of high versus low CB(1) receptor density in a ratio of 1.6. The displaceable radioactivity of one enantiomer in the brains of mice determined in a pretreatment study using the CB(1) antagonist N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) was nearly double that of the racemate for the same determination; therefore, the active enantiomer is a candidate for PET studies in animals. A pretreatement study for the other enantiomer found no displaceable radioactivity in the same group of mice; this result suggested the enantiomer was inactive.
authors.affiliation: Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA. pwillis@intra.nida.nih.gov
authors.forename: Peter G
authors.initials: PG
authors.lastname: Willis
authors.forename: Olga A
authors.initials: OA
authors.lastname: Pavlova
authors.forename: Svetlana I
authors.initials: SI
authors.lastname: Chefer
authors.forename: D Bruce
authors.initials: DB
authors.lastname: Vaupel
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Mukhin
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D005462:Fluorine Radioisotopes; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C504989:3-(4-fluoronaphthoyl)1-(N-methylpiperidin-2-ylmethyl)indole; D005462:Fluorine Radioisotopes; D007211:Indoles; D008024:Ligands; D010880:Piperidines; D019275:Radiopharmaceuticals; D043884:Receptor, Cannabinoid, CB1