title: Synthesis, receptor potency, and selectivity of halogenated diphenylpiperidines as serotonin 5-HT2A ligands for PET or SPECT brain imaging.
abstract: A series of 4'-substituted phenyl-4-piperidinylmethanol and benzoyl-4-piperidine derivatives was synthesized as potential novel serotonin 5-HT2A receptor ligands that can be radiolabeled for in vivo brain imaging. Compounds were prepared by alkylation of 4-substituted benzoyl-4-piperidine with an iodo- or fluoro-substituted phenylalkyl halide followed by reduction with sodium borohydride. Potency of novel compounds was determined by in vitro radioreceptor affinity assays selective for serotonin 5-HT2A receptors. Potent compounds were further evaluated for selectivity at serotonin-2A versus 2C, 6, and 7, as well as dopamine D2 and adrenergic alpha1 and alpha2 receptors. The novel compound (4-fluorophenyl)-(1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl])methanol was particularly promising with high 5-HT2A potency (K(i) = 1.63 nM) and >300-fold selectivity over other 5-HT receptor types.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine and VA Connecticut Health Care Service, West Haven, Connecticut 06516, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Fu
authors.forename: Ping-Zhong
authors.initials: PZ
authors.lastname: Tan
authors.forename: Nora S
authors.initials: NS
authors.lastname: Kula
authors.forename: Ross
authors.initials: R
authors.lastname: Baldessarini
authors.forename: Gilles
authors.initials: G
authors.lastname: Tamagnan
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Baldwin
mesh_terms: D000818:Animals; D019556:COS Cells; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014055:Tomography, Emission-Computed; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C455824:(4-fluorophenyl)-(1-(2-(4-fluorophenyl)ethyl)piperidin-4-yl)methanol; D008024:Ligands; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor; C104425:serotonin 7 receptor