SYNTHESIS AND BINDING-PROPERTIES OF THE FLUORINATED SUBSTITUTED BENZAMIDE [H-3] NCQ-115, A NEW SELECTIVE DOPAMINE-D2 RECEPTOR LIGAND

[H-3]NCQ 115 ((R)-5-bromo-2,3-dimethoxy-N-((1-([2,5-H-3]-4-fluorobenzyl)-2-pyrrolidinyl)methyl)benzamide) was prepared by acylation of (R)-(2-aminomethyl)-1-([2,5-H-3]-4-fluorobenzyl)pyrrolidine, which was obtained in a stereoconservative synthesis from (R)-prolinamide. Purification by reversed phase high performance liquid chromatography (HPLC) gave [H-3]NCQ 115 with a radiochemical purity of > 99% and a specific activity of 0.97 GBq/mu-mol (36 Ci/mmol). Saturation analyses, association and dissociation kinetics as well as binding competition with several compounds of various classes were performed with [H-3]NCQ 115 in rat striatal homogenates. Saturation analyses in vitro showed that [H-3]NCQ 115 bound to a single binding site with a K(d) = 214 pM and B(max), = 35.4 fmol/mg. The binding of [H-3]NCQ 115 was dependent upon sodium ions, since the number of binding sites was altered when sodium ions were excluded from the incubation medium. NCQ 115 inhibited the binding of [H-3]raclopride to dopamine D2 receptors with high affinity (K(i) = 147 pM), having much lower affinity for other receptors. The affinity of this substituted 1-benzyl-2-pyrrolidinylmethyl benzamide was confined to the (R)-enantiomer, which contrasts with that of the corresponding N-ethyl derivatives such as FLB 457, raclopride, eticlopride, sulpiride and NCQ 298, where the pharmacological activity is found in the (S)-enantiomer. It can be concluded that [H-3]NCQ 115 binds to dopamine D2 receptors in the rat striatum with high affinity and high selectivity. [H-3]NCQ 115 can also be used for in vivo binding studies of the brain. [F-18]NCQ 115 may be a suitable ligand for positron emission tomography (PET) studies of the human brain in vivo.