title: N-(N-benzylpiperidin-4-yl)-2-[18F]fluorobenzamide: a potential ligand for PET imaging of sigma receptors.
abstract: Four nitro- and fluorobenzamides (1-4) have been synthesized in good yields from nitro- and fluoro-substituted benzoyl chloride with 4-amino-1-benzylpiperidine. In vitro studies showed that these compounds have high affinities to sigma receptors. N-(N-Benzylpiperidin-4-yl)-2-fluorobenzamide (3), in particular, bound to sigma receptors with high affinity (Ki = 3.4 nM, guinea pig brain membranes) and high selectivity (sigma-2/sigma-1 = 120). It was, therefore, labeled with 18F and evaluated as a sigma receptor radioligand. N-(N-Benzylpiperidin-4-yl)-2-[18F]fluorobenzamide (3a) was synthesized in one step by nucleophile substitution of the 2-nitro precursor (1) with [18F]fluoride in DMSO at 140 degrees C for 20 min followed by purification with HPLC in 4-10% yield (decay corrected). The synthesis time was 90 min and the specific activity was 0.4-1.0 Ci/mumol. Tissue distribution in mice revealed that the uptakes of 3a in the brain, heart, liver, lungs, spleen, kidneys and small intestine were high, and the radioactivity in these organs remained constant from 60 to 120 min post-injection. The radioactivity in the bone did not significantly increase, suggesting in vivo defluorination may not be the major route of metabolism of 3a in mice. Blocking studies with haloperidol in rats indicated that the uptake of compound 3a in the rat brain was selective to haloperidol-sensitive sigma sites. These results suggest that compound 3a is a potent sigma receptor radioligand and may be a potential ligand for PET imaging of sigma receptors in humans.
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: C Y
authors.initials: CY
authors.lastname: Shiue
authors.forename: G G
authors.initials: GG
authors.lastname: Shiue
authors.forename: S X
authors.initials: SX
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Wilder
authors.forename: J H
authors.initials: JH
authors.lastname: Greenberg
authors.forename: F
authors.initials: F
authors.lastname: Benard
authors.forename: J A
authors.initials: JA
authors.lastname: Wortman
authors.forename: A A
authors.initials: AA
authors.lastname: Alavi
mesh_terms: D000818:Animals; D001549:Benzamides; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects; D001923:Brain Chemistry; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005462:Fluorine Radioisotopes; D006168:Guinea Pigs; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D051379:Mice; D010880:Piperidines; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D001549:Benzamides; D005462:Fluorine Radioisotopes; D008024:Ligands; C109873:N-(N-benzylpiperidin-4-yl)-2-fluorobenzamide; D010880:Piperidines; D017480:Receptors, sigma