RAT-BRAIN BINDING-SITES FOR PRAMIPEXOLE, A CLINICALLY USEFUL D-3-PREFERRING DOPAMINE AGONIST

Pramipexole (PPX) is currently being evaluated for treatment of schizo phrenia and Parkinson's disease. In studies with cloned subtypes of th e dopamine (DA) D2 receptor subfamily, PPX has higher affinity for the D-3 compared to the D-2 and D-4 subtypes; unlike 7-[H-3]hydroxy-N,N-d i-n-propyl-2-aminotetralin (7-OH-DPAT), it does not bind to sigma site s. Receptor binding autoradiography with [H-3]PPX (5 nM, 62 Ci/mmol) w as used to evaluate the distribution of PPX binding sites within the r at brain. Consistent with its preference for D-3-binding sites, the hi ghest concentrations of [H-3]PPX binding sites were found in the islet s of Calleja (ICj), previously reported to contain D-3 but not D-2 or D-4 mRNA. [H-3]PPX binding was also high in other mesolimbic areas suc h as the nucleus accumbens (N, accum), olfactory tubercle, and amygdal a. [H-3]PPX binding was also high in caudate (Cd), although slightly l ess than in mesolimbic areas. Less [H-3]PPX binding sites were found i n ventral tegmental area (VTA) and substantia nigra, areas rich in cel l bodies for DA neurons. Thus, although PPX most potently stimulates D A autoreceptors, PPX binding sites have their highest concentrations i n projection areas containing both DA terminal and postsynaptic recept ors. Because of PPX's preferential affinity for the Dg receptor subtyp e and its resultant high mesolimbic binding, it could have a unique th erapeutic profile for treatment of psychiatric and/or neurological dis eases.