title: Synthesis, in vitro binding profile and biodistribution of a 125I-labeled N-benzyl pyrrolidinyl benzamide derivative: a potential radioligand for mapping dopamine D2 receptors.
abstract: cis-N-(1-Benzyl-2-methylpyrrolidine-3-yl)-5-iodo-2-methoxy-4-(methylamin o) benzamide (IYM), a YM-09151-2 analog iodinated at the 5-position of the benzoyl moiety, was synthesized and evaluated as a potential radiopharmaceutical for investigating brain dopamine D2 receptors by single photon emission computer tomography (SPECT). [125I]IYM was synthesized by a halogen exchange reaction and purified by high-performance liquid chromatography (HPLC). An in vitro competitive binding study with [3H]spiperone using rat striatal synaptosomal membranes revealed that IYM had higher affinity for dopamine D2 receptors than did YM-09151-2 or spiperone. In a saturation binding study using rat striatal synaptosomal membranes, IYM had a Kd of 0.04 nM. Biodistribution studies in mice disclosed that [125I]IYM exhibited high and specific striatal uptake, with the striatal/cerebellar uptake ratio being 14 at 120 min after injection. Furthermore, the striatal uptake of [125I]IYM was saturable, and [125I]IYM was displaced only by dopaminergic compounds. Ex vivo autoradiographic studies in rats further confirmed the high uptake and retention of this agent in the striatum and total blockade of its uptake by YM-09151-2. Thus, IYM showed specific binding to dopamine D2 receptors in the rodent striatum and therefore holds great potential for use in in vivo dopamine D2 receptor studies.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Saji
authors.forename: K
authors.initials: K
authors.lastname: Tanahashi
authors.forename: T
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Y
authors.initials: Y
authors.lastname: Iida
authors.forename: Y
authors.initials: Y
authors.lastname: Magata
authors.forename: A
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D001345:Autoradiography; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015259:Dopamine Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D018492:Dopamine Antagonists / Q000737:chemistry / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D001549:Benzamides; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D007457:Iodine Radioisotopes; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D013134:Spiperone; C030265:nemonapride