Electrophysiological Study, Biodistribution in Mice, and Preliminary PET Evaluation in a Rhesus Monkey of 1-Amino-3-[F]fluoromethyl-5-methyl-adamantane (F-MEM): A Potential Radioligand for Mapping the NMDA-Receptor Complex

The effect of the fluorinated memantine derivative and NMDA receptor antagonist, 1-amino-3-fluoromethyl-5-methyl-adamantane (F-MEM), at the NMDA receptor ion channel was studied by patch clamp recording. The results showed that F-MEM is a moderate NMDA receptor channel blocker. A procedure for the routine preparation of the F-labelled analog F-MEM has been developed using a two-step reaction sequence. This involves the no-carrier-added nucleophilic radiofluorination of 1-[N-(tertbutyloxy)carbamoyl]-3-(toluenesulfonyloxy)methyl-5-methyl-adamantane and the subsequent cleavage of the BOC-protecting group using aqueous HCl. The F-MEM was obtained in 22 6 7% radiochemical yield (decay-corrected to EOB) in a total synthesis time including HPLC purification of 90 min. A biodistribution study after IV injection of F-MEM in mice showed a fast clearance of radioactivity from blood and relatively high initial uptake in the kidney and in the lung, which gradually decreased with time. The brain uptake was high (up to 3.6% ID/g, 60 min postinjection) with increasing brain-blood ratios: 2.40, 5.10, 6.33, and 9.27 at 5, 30, 60, and 120 min, respectively. The regional accumulation of the radioactivity in the mouse brain was consistent with the known distribution of the PCP recognition site. Preliminary PET evaluation of the radiotracer in a rhesus monkey demonstrated good uptake and prolonged retention in the brain, with a plateau from 35 min onwards p.i. in the NMDA receptor-rich regions (frontal cortex, striata, and temporal cortex). Delineation of the hippocampus, a region known to contain a high density of NMDA receptors, was not possible owing to the resolution of the PET tomograph. The regional brain uptake of F-MEM was changed by memantine and by a pharmacological dose of (1)-MK-801, indicating competition for the same binding sites. In a preliminary experiment, haloperidol, a dopamine D2 and sigma receptor antagonist, decreased the binding of F-MEM from the brain regions examined, suggesting that binding was also occurring to the sigma recognition sites. NUCL MED BIOL 25;4:323–330, 1998. © 1998 Elsevier Science Inc.