Synthesis and binding properties of the fluorinated substituted benzamide [3H]NCQ 115, a new selective dopamine D2 receptor ligand.
[3H]NCQ 115 [R)-5-bromo-2,3-dimethoxy-N-[1-([2,5-3H]-4- fluorobenzyl)-2-pyrrolidinyl)methyl)benzamide) was prepared by acylation of (R)-(2-aminomethyl)-1- ([2,5-3H]-4-fluorobenzyl)pyrrolidine, which was obtained in a stereo-conservative synthesis from (R)-prolinamide. Purification by reversed phase high performance liquid chromatography (HPLC) gave [3H]NCQ 115 with a radiochemical purity of greater than 99% and a specific activity of 0.97 GBq/mumol (36 Ci/mmol). Saturation analyses, association and dissociation kinetics as well as binding competition with several compounds of various classes were performed with [3H]NCQ 115 in rat striatal homogenates. Saturation analyses in vitro showed that [3H]NCQ 115 bound to a single binding site with a Kd = 214 pM and Bmax = 35.4 fmol/mg. The binding of [3H]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 [3H]raclopride to dopamine D2 receptors with high affinity (Ki = 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 [3H]NCQ 115 binds to dopamine D2 receptors in the rat striatum with high affinity and high selectivity. [3H]NCQ 115 can also be used for in vivo binding studies of the brain. [18F]NCQ 115 may be a suitable ligand for positron emission tomography (PET) studies of the human brain in vivo.
Hall
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CNS2 Research and Development, Astra Research Centre AB, Södertälje, Sweden.
Högberg
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T
Halldin
C
C
Bengtsson
S
S
Wedel
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I
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000378:metabolism*; D015259:Dopamine Agents / Q000378:metabolism / Q000494:pharmacology; D018492:Dopamine Antagonists; D066298:In Vitro Techniques; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D020891:Raclopride; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism*; D017448:Receptors, Dopamine D2; D012457:Salicylamides / Q000378:metabolism / Q000494:pharmacology; D012964:Sodium / Q000494:pharmacology; D013134:Spiperone / Q000378:metabolism; D013237:Stereoisomerism
D001549:Benzamides; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D011759:Pyrrolidines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D012457:Salicylamides; C073230:5-bromo-2,3-dimethoxy-N-((1-(4-fluorobenzyl)-2-pyrrolidinyl)methyl)benzamide; D020891:Raclopride; D013134:Spiperone; D012964:Sodium