We previously synthesized cyclofoxy, a fluoro analogue of the potent narcotic antagonist naltrexone, and showed the compound bound with high affinity to opiate receptors in vitro. This compound has now been tritiated to a specific activity of 16.4 Ci/mmol by mercuric oxide oxidation to the delta 15,16 dehydro derivative followed by palladium-catalysed reduction with carrier free tritium. Methodology has also been developed for synthesis of high specific activity 3-acetylcyclofoxy labeled with positron emitting [fluorine-18] for PETT imaging studies. The method utilizes reactor-produced [fluorine-18] as its tetraethylammonium (TEA-F) salt in a SN2 displacement on a secondary triflate precursor. Typically, 45% of the [fluorine-18] activity can be converted to the reactive TEAF in a 70 min preparation. From this, 35% yield (decay corrected) of the [fluorine-18] 3-acetylcyclofoxy was obtained after HPLC purification with a specific activity of 25 Ci/mmol in a total synthesis time of 60 min. [Fluorine-18] 3-acetylcyclofoxy accumulation in opiate receptor rich brain regions of both rat and baboon was shown to be completely displaced by the active enantiomer of naloxone ((-)-naloxone) while the identical dose of the pharmacologically inert (+)-naloxone has no detectable effect. Autoradiographic studies with tritiated cyclofoxy in rat brain slices have revealed that the compound labels a population of opiate receptors virtually identical to that labeled by naloxone. These and our previous results indicate that cyclofoxy is an excellent tool to study the physiological role of opiate receptors in living animals, and in humans using PETT imaging.
