title: NCQ 298, a new selective iodinated salicylamide ligand for the labelling of dopamine D2 receptors.
abstract: NCQ 298 ((S)-3-iodo-N-[(l-ethyl-2-pyrrolidinyl)methyl]-5,6- dimethoxysalicylamide) has an iodine substituent. We have labelled NCQ 298 with 123I and 125I, and used the radioligands as tracers in receptor studies in vitro, in vivo in autoradiography and in SPECT studies on Cynomolgus monkeys. [125I]NCQ 298 bound in vitro to a single binding site with a KD = 19 pM. NCQ 298 has thus a 10-fold higher affinity for the dopamine D2 receptors than the corresponding des-5-methoxy compound FLA 961 (IBZM), previously used in SPECT studies. The binding of [125I]NCQ 298 was entirely reversible (T1/2 = 17.5 min at 37 degrees C). Autoradiographical studies in vitro on rat and monkey brain tissue sections showed a distinct binding in caudate-putamen, nucleus accumbens, substantia nigra, and in layer 5 of the cerebral cortex. In vivo binding studies in mice showed a ratio of 10 between [125I]NCQ 298 binding in striatum and cerebellum. Binding was displaced by the selective dopamine D2 receptor antagonist raclopride. In SPECT studies with [123I]NCQ 298 in two Cynomolgus monkeys, radioactivity accumulated in the basal ganglia. The measured striatum to cerebellum ratio was about 15 after 3 h. A monkey brain phantom was constructed for the determination of conversion factors from pixel events to actual radioactivity. The resulting, corrected striatum to cerebellum ratio obtained was 30. After administration of 12 mg raclo-pride to one of the monkeys there was a substantial decrease in striatal radioactivity. [125I]NCQ 298 is a suitable ligand for the labelling of dopamine D2 receptors in vitro and in vivo. The specific properties of [123I]NCQ 298 suggest that this compound is a useful ligand for quantitative SPECT studies of dopamine D2 receptors in man.
authors.affiliation: CNS2 Research and Development, Astra Research Centre AB, Södertälje, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Hall
authors.forename: T
authors.initials: T
authors.lastname: Högberg
authors.forename: C
authors.initials: C
authors.lastname: Halldin
authors.forename: C
authors.initials: C
authors.lastname: Köhler
authors.forename: P
authors.initials: P
authors.lastname: Ström
authors.forename: S B
authors.initials: SB
authors.lastname: Ross
authors.forename: S A
authors.initials: SA
authors.lastname: Larsson
authors.forename: L
authors.initials: L
authors.lastname: Farde
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D015259:Dopamine Agents / Q000493:pharmacokinetics; D018492:Dopamine Antagonists; D007457:Iodine Radioisotopes; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D020891:Raclopride; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D012457:Salicylamides / Q000378:metabolism / Q000493:pharmacokinetics; D012964:Sodium / Q000502:physiology; D013045:Species Specificity; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D015259:Dopamine Agents; D018492:Dopamine Antagonists; D007457:Iodine Radioisotopes; D011954:Receptors, Dopamine; D012457:Salicylamides; D020891:Raclopride; D012964:Sodium; C064246:NCQ 298