DOPAMINE-RECEPTORS LABELED BY PHNO

Since the high-affinity state of dopamine D2 receptors may be abnormal in psychomotor diseases, it is desirable to develop a radioactive ago nist to label this high-affinity site for possible clinical diagnostic use. (+)PHNO is a selective D2 agonist used to treat Parkinson's dise ase. We prepared H-3!(+)PHNO from allyl-des-propyl-(+)PHNO. In bindin g to dopamine receptors in homogenates of canine brain striata, H-3!( +)PHNO had a dissociation constant of 0.35 nM in the absence of NaCl, and 0.56 nM in the presence of NaCl. Dopamine agonists and antagonists inhibited the binding of H-3!(+)PHNO at drug concentrations similar to those inhibiting other H-3!ligands at D2 receptors, but not simila r to those acting at D4 receptors. Approximately 90% of the total H-3 !(+)PHNO binding was specific. Guanilylimidodiphosphate markedly inhib ited H-3!(+)PHNO binding, suggesting that H-3!(+)PHNO was binding pr imarily to the high-affinity state of dopamine D2 receptors rather tha n to D3 receptors. The density of the H-3!(+)PHNO binding sites was e qual to that of H-3!emonapride (or H-3!YM-09151-2), both densities o f which were 1.5- to 2-fold higher than that of H-3!spiperone, compat ible with the idea that H-3!(+)PHNO binds to monomers of D2, while H -3!spiperone binds to dimers of D2. Although H-3!(+)PHNO has good sel ectivity and affinity for the high-affinity state of D2, the H-3!liga nd was sensitive to endogenous dopamine, since washing the tissue lowe red the dissociation constant. For future in vivo labelling of D2 by a n agonist, therefore, it will be essential to search for a related H- 3!ligand with an even lower dissociation constant. (C) 1993 Wiley-Liss , Inc.