title: Design, synthesis, radiolabeling, and in vivo evaluation of carbon-11 labeled N-[2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a potential positron emission tomography tracer for the dopamine D(4) receptors.
abstract: Here we describe the design, synthesis, and evaluation of physicochemical and pharmacological properties of D(4) dopamine receptor ligands related to N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (2). Structural features were incorporated to increase affinity for the target receptor, to improve selectivity over D(2) and σ(1) receptors, to enable labeling with carbon-11 or fluorine-18, and to adjust lipophilicity within the range considered optimal for brain penetration and low nonspecific binding. Compounds 7 and 13 showed the overall best characteristics: nanomolar affinity for the D(4) receptor, >100-fold selectivity over D(2) and D(3) dopamine receptors, 5-HT(1A), 5-HT(2A), and 5-HT(2C) serotonin receptors and σ(1) receptors, and log P = 2.37-2.55. Following intraperitoneal administration in mice, both compounds rapidly entered the central nervous system. The methoxy of N-[2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide (7) was radiolabeled with carbon-11 and subjected to PET analysis in non-human primate. [(11)C]7 time-dependently accumulated to saturation in the posterior eye in the region of the retina, a tissue containing a high density of D(4) receptors.
authors.affiliation: Dipartimento Farmaco-Chimico, Università degli Studi di Bari A Moro, Via Orabona 4, 70125 Bari, Italy.
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
authors.forename: Paola
authors.initials: P
authors.lastname: De Giorgio
authors.forename: Irene T
authors.initials: IT
authors.lastname: Lee
authors.forename: Sean I
authors.initials: SI
authors.lastname: Rodeheaver
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Weiss
authors.forename: Claudia
authors.initials: C
authors.lastname: Fracasso
authors.forename: Silvio
authors.initials: S
authors.lastname: Caccia
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.forename: John A
authors.initials: JA
authors.lastname: Schetz
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D007553:Isotope Labeling; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D012160:Retina / Q000000981:diagnostic imaging / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D001549:Benzamides; D002250:Carbon Radioisotopes; D008024:Ligands; C553262:N-(2-(4-(3-cyanopyridin-2-yl)piperazin-1-yl)ethyl)-3-methoxybenzamide; D009570:Nitriles; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D050638:Receptors, Dopamine D4