New Dopamine D2 Receptor Agonist, [3H]MCL-536, for Detecting Dopamine D2high Receptors in Vivo.

Increases in the D2 receptor high affinity state are associated with certain neurological disorders. We synthesized and characterized the high-affinity D2high ligand [3H]MCL-536 in competition binding against the D2/3 agonist R-(−)-N-n-propylnorapomorphine (NPA) and the D2/3 antagonist raclopride. The total binding of [3H]MCL-536 (minus that in the presence of 100 nM NPA) was measured by saturation binding in CHO cells expressing human D2long; the data yielded separable, nonsaturable nonspecific, and saturable specific components. The former represents an aporphine site common to NPA and [3H]MCL-536. The latter indicated specific binding to the total D2 receptors (both high and low-affinity states). [3H]MCL-536 had a Kd of 0.8 nM. In competition binding, NPA had a Ki of 0.16 nM, and raclopride had a Ki of 0.9 nM. Co-incubation with guanylylimidodiphosphate abolished binding to D2high. This unique profile makes radiolabeled MCL-536 a versatile tool for diagnostics and therapeutics, and may quantify D2high ...