Faculty Bibliography

BMY 14802 is a compound containing fluorine developed as a potential antipsychotic drug. It has a moderate affinity for the sigma binding site and a very low affinity for dopamine D2 receptors and has been predicted to have antipsychotic properties without the side effect potential of existing drugs. To assess the brain uptake, pharmacokinetics, stereoselectivity and binding properties of this potential antipsychotic drug, enantiomerically pure samples of (-) and (+)-[18F]BMY 14802 were examined in a baboon with PET. A tissue distribution with racemic labeled BMY 14802 was also carried out in mice. Radiochemical yields of 15% at the end of bombardment (EOB) for the racemic mixture, and 5% for each enantiomer with a specific activity of 2-5 Ci/mumol at EOB were obtained. In baboons, [18F]BMY 14802 cleared rapidly from the plasma and the glucuronidated [18F]BMY 14802 appeared. Radioactivity peaked (0.04-0.07% dose/cc) in all areas of the brain examined at about 5 min postinjection. It then rapidly cleared to about 30% of peak value by 20 min postinjection and to less than 10% of peak by 60 min postinjection in all regions. A similar rapid clearance from brain was also observed in mice. Pretreatment with unlabeled BMY 14802 (7 mg/kg), did not produce the expected reductions in distribution volume and clearance halftimes consistent with receptor binding. Although the rapid kinetics of [18F]BMY 14802 made it difficult to resolve the processes of transport and binding of the labeled drug, the lack of regional distribution consistent with the known distribution of sigma binding sites as well as the lack of stereoselectivity suggest that the behavior of BMY 14802 in the brain is dominated by its transport properties in tissue rather than its binding to sigma sites. Moreover, its rapid clearance from brain may be a limiting factor in its use as an antipsychotic drug

The first example of a no-carrier-added 18F-labeled catecholamine, 6-[18F]fluoronorepinephrine (6-[18F]FNE), has been synthesized via nucleophilic aromatic substitution. The racemic mixture was resolved on a chiral HPLC column to obtain pure samples of (-)-6-[18F]FNE and (+)6-[18F]FNE. Radiochemical yields of 20% at the end of bombardment (EOB) for the racemic mixture (synthesis time 93 min), 6% for each enantiomer (synthesis time 128 min) with a specific activity of 2-5 Ci/mumol at EOB were obtained. Chiral HPLC peak assignment for the resolved enantiomers was achieved by using two independent methods: polarimetric determination and reaction with dopamine beta-hydroxylase. Positron emission tomography (PET) studies with racemic 6-[18F]FNE show high uptake and retention in the baboon heart. This work demonstrates that nucleophilic aromatic substitution by [18F]fluoride ion is applicable to systems having electron-rich aromatic rings, leading to high specific activity radiopharmaceuticals. Furthermore, the suitably protected dihydroxynitrobenzaldehyde 1 may serve as a useful synthetic precursor for the radiosynthesis of other complex 18F-labeled radiotracers