title: II. Localization and characterization of dopamine D4 binding sites in rat and human brain by use of the novel, D4 receptor-selective ligand [3H]NGD 94-1.
abstract: The dopamine D4 selective ligand, [H]NGD 94-1, was used in these studies to characterize binding sites in rat and human brain tissue by membrane binding and autoradiography techniques. Autoradiographic analysis of rat brain showed that specific [3H]NGD 94-1 binding was greatest in entorhinal cortex, lateral septal nucleus, hippocampus and the medial preoptic area of the hypothalamus. This nonstriatal distribution of [3H]NGD 94-1 binding was distinct from the autoradiographic distribution of dopamine D2 and D3 receptor subtypes. In homogenate preparations from rat brain regions, [3H]NGD 94-1 binding sites were low in density (<30.0 fmol/mg protein). The low density of D4 binding sites was corroborated by autoradiographic comparisons in which binding density for D4 receptors as measured by [3H]NGD 94-1 was only 1/7 of D2 and 1/5 of D3 receptor densities, despite corrections for differing radioligand binding characteristics. Pharmacological evaluation showed high affinity at rat [3H]NGD 94-1 binding sites for compounds with known D4 receptor affinity and little displacement by compounds with affinity for dopamine D1/D2/D3 receptor subtypes. Specific, high-affinity [3H]NGD 94-1 binding was also present in several human brain regions, including hippocampus, hypothalamus, dorsal medial thalamus, entorhinal cortex, prefrontal cortex and lateral septal nucleus. High-affinity [3H]NGD 94-1 binding was not present in any human striatal region examined. The pharmacological profile of [3H]NGD 94-1 binding sites in human brain was consistent with that previously demonstrated for cloned human D4 receptors expressed in mammalian cells. These findings suggest that specific, high-affinity [3H]NGD 94-1 binding exists in rat and human brain and that these sites reflect populations of dopamine D4 receptors with a distribution unique among dopamine receptor subtypes.
authors.affiliation: Neurogen Corporation, Branford, Connecticut 06405, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Primus
authors.forename: A
authors.initials: A
authors.lastname: Thurkauf
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: E
authors.initials: E
authors.lastname: Yevich
authors.forename: S
authors.initials: S
authors.lastname: McInerney
authors.forename: K
authors.initials: K
authors.lastname: Shaw
authors.forename: J F
authors.initials: JF
authors.lastname: Tallman
authors.forename: D W
authors.initials: DW
authors.lastname: Gallagher
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D008297:Male; D011743:Pyrimidines / Q000378:metabolism*; D020891:Raclopride; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050638:Receptors, Dopamine D4; D012457:Salicylamides / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000378:metabolism; D014316:Tritium
chemical_list: C493599:DRD4 protein, human; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493601:Drd4 protein, rat; D007093:Imidazoles; D011743:Pyrimidines; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D013764:Tetrahydronaphthalenes; D014316:Tritium; D050638:Receptors, Dopamine D4; C107692:NGD 94-1; D020891:Raclopride; C031349:7-hydroxy-2-N,N-dipropylaminotetralin