title: Synthesis, ex vivo evaluation, and radiolabeling of potent 1,5-diphenylpyrrolidin-2-one cannabinoid subtype-1 receptor ligands as candidates for in vivo imaging.
abstract: We have reported that [methyl- (11)C] (3 R,5 R)-5-(3-methoxyphenyl)-3-[(R)-1-phenylethylamino]-1-(4-trifluoromethylphenyl)pyrrolidin-2-one ([(11)C] 8, [(11)C]MePPEP) binds with high selectivity to cannabinoid type-1 (CB 1) receptors in monkey brain in vivo. We now describe the synthesis of 8 and four analogues, namely, the 4-fluorophenyl (16, FMePPEP), 3-fluoromethoxy (20, FMPEP), 3-fluoromethoxy- d 2 (21, FMPEP- d 2), and 3-fluoroethoxy analogues (22, FEPEP), and report their activity in an ex vivo model designed to identify compounds suitable for use as positron emission tomography (PET) ligands. These ligands exhibited high, selective potency at CB 1 receptors in vitro (K b < 1 nM). Each ligand (30 microg/kg, iv) was injected into rats under baseline and pretreatment conditions (3, rimonabant, 10 mg/kg, iv) and quantified at later times in frontal cortex ex vivo with liquid chromatography-mass spectrometry (LC-MS) detection. Maximal ligand uptakes were high (22.6-48.0 ng/g). Under pretreatment, maximal brain uptakes were greatly reduced (6.5-17.3 ng/g). Since each ligand readily entered brain and bound with high selectivity to CB 1 receptors, we then established and here describe methods for producing [(11)C] 8, [(11)C] 16, and [(18)F] 20- 22 in adequate activities for evaluation as candidate PET radioligands in vivo.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Donohue
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Krushinski
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Eyassu
authors.initials: E
authors.lastname: Chernet
authors.forename: Lee
authors.initials: L
authors.lastname: Phebus
authors.forename: Amy K
authors.initials: AK
authors.lastname: Chesterfield
authors.forename: Christian C
authors.initials: CC
authors.lastname: Felder
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: John M
authors.initials: JM
authors.lastname: Schaus
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D049268:Positron-Emission Tomography; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D008024:Ligands; D011760:Pyrrolidinones; D043884:Receptor, Cannabinoid, CB1
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