DEVELOPMENT OF RADIOPHARMACEUTICALS FOR IMAGING THE NMDA RECEPTOR FUNCTIONS

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There has been great interest in the development of useful radioligands for imaging the NMDA receptor in living human brain by non-invasive tomographic techniques. New fluorine-18 labelled derivatives of thienylcyclohexylpiperidine (TCP), a noncompetitive antagonist of NMDA receptor, which binds to the phencyclidine (PCP) binding site located within the receptor-associated ion channel, have been synthesized. The mesylate precursors for (1S^*,2R^*) -2- (hydroxymethyl) -and (1S^*,2R^*) -2- (methoxymethoxymethyl) -1- (N-piperidyl) -1- [2- (2'-[^<18>F] fluoroethyl) thiophenyl] cyclohexane, respectively, were prepared from 2-hydroxycyclohexanone. Radiochemical syntheses were done by displacement of the mesylates by [^<18>F] fluoride ion with no-carrier-added [K/2.2.2] ^<+18>F in 4-4.5%radiochemical yields with specific activity of>31GBq/mol. In the biodistribution studies with these ^<18>F-radioligands, no specifc accumulation of radioactivity was observed and blocking effect of 1- [1- (2-thienyl) -2-hydroxy-methylcyclohexyl] piperidine (cis-HPTC) was not found for all the tissues investigated, clearly indicating that the radioactivity was distributed due to non-selective binding. Low affinities of these ligands to the NMDA receptor were also shown in vitro binding experiemnts. ln conclusion, it turned out that the new ligands were not suitable as in vivo radioligands for PET studies of NMDA receptor. lt will be necessary to use more hydrophilic molecules as lead compounds for developing useful in vivo radioligands for NMDA receptor.