HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ding, Y.-S. Articles by Taylor, D. P. Search for Related Content PubMed PubMed Citation Articles by Ding, Y.-S. Articles by Taylor, D. P.

Synthesis and PET Studies of Fluorine-18-BMY 14802: A Potential Antipsychotic Drug

Department of Chemistry, Brookhaven National Laboratory, Upton, New York
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut

Correspondence: For correspondence or reprints contact: Dr. Yu-Shin Ding, Dept. of Chemistry, Brookhaven National Laboratory, Bldg. 555, Lewis Road, Upton, NY 11973.

ABSTRACT

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/µmol 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 post-injection 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 an as antipsychotic drug.