title: Syntheses of [123I]-, [125I]- and unlabelled (S)-3-iodo-5,6-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]salicylamide (NCQ 298), selective ligands for the study of dopamine D-2 receptors.
abstract: The salicylamide NCQ 298, (S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylami de (4), binds with a high affinity and selectivity to central dopamine D-2 receptors. In the present paper the synthesis of NCQ 298 and the efficient labelling both with 123I and 125I are described. The unlabelled NCQ 298 was synthesized by iodination of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,5,6-trimethoxybenzamide followed by demethylation with boron tribromide, which produced 4 and the regioisomer 5 in a ratio of 82:18. The two isomeric salicylamides were separated by radial chromatography and tested for their abilities to inhibit the binding of [3H]raclopride to rat striatal membranes in vitro in relation to some representative salicylamides. The 5,6-dimethoxysalicylamide 4 (NCQ 298) was found to be considerably more active than the corresponding 6-methoxysalicylamide 10 (FLA 961 or IBZM). The radioligands [123I]NCQ 298 and [125I]NCQ 298 were prepared in a carrier-free form from the corresponding desiodo compound by the chloramine-T protocol and isolated by semipreparative HPLC. The total radiochemical yields of [123I]NCQ 298 and [125I]NCQ 298 (based on [123I]- and [125I]iodide and decay-corrected) were 88% and 93%, respectively, with a radiochemical purity of greater than 99%. [125I]NCQ 298 will be studied to evaluate its potential as a radioligand in studies requiring a high specific activity, selectivity and high potency to label dopamine D-2 receptors. [123I]NCQ 298 has potential as a radioligand for the in vivo examination of central dopamine D-2 receptors in human brain by Single Photon Emission Computed Tomography (SPECT).
authors.affiliation: CNS2 Research & Development, Astra Research Centre AB, Södertälje, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Högberg
authors.forename: P
authors.initials: P
authors.lastname: Ström
authors.forename: H
authors.initials: H
authors.lastname: Hall
authors.forename: C
authors.initials: C
authors.lastname: Köhler
authors.forename: C
authors.initials: C
authors.lastname: Halldin
authors.forename: L
authors.initials: L
authors.lastname: Farde
mesh_terms: D000818:Animals; D015259:Dopamine Agents / Q000138:chemical synthesis*; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D020891:Raclopride; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D012457:Salicylamides / Q000138:chemical synthesis* / Q000378:metabolism
chemical_list: D015259:Dopamine Agents; D007457:Iodine Radioisotopes; D011954:Receptors, Dopamine; D012457:Salicylamides; D020891:Raclopride; C064246:NCQ 298