Hydrophobicity predicts in vivo 19F magnetic resonance detectability of fluorinated psychiatric drugs: simple test for likely success in clinical pharmacokinetic studies

Abstract

AbstractThe 19F NMR signal half‐height linewidths of six fluorinated psychiatric pharmaceuticals, on which successful in vivo magnetic resonance (MR) studies have been reported (fenfluramine, fluvoxamine, fluoxetine, trifluoperazine, phenfluramine, and paroxetine), were measured at 0.3 mM concentration in an artificial biofluid consisting of aqueous isotonic neutral phosphate‐buffered saline and 5% w/v bovine serum albumin. For the first five, which contain trifluoromethyl groups, linewidth is strongly positively correlated (R2=0.95) with calculated water: n‐octanol distribution coefficient at pH7 (cLogDpH7) by the relationship: Linewidth (Hz)=38cLogDpH7+5. This suggests that simple measurements, or calculations, feasible in most chemical laboratories, predict in vivo signal linewidth and hence the likely ease with which a development compound would be detected in clinical trials of brain pharmacokinetics. The procedures are available to all drug development organizations and should help establish confidence, or no‐go decisions, about committing major resources to MR pharmacokinetic studies on human subjects. Drug Dev Res 69:279–283, 2008 © 2008 Wiley‐Liss, Inc.