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

Abstract

The 19 F 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 (R 2 5 0.95) with calculated water: n-octanol distribution coefficient at pH7 (cLogD pH7 ) by the relationship: Linewidth (Hz) 5 38cLogD pH7 15. 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][280][281][282][283] 2008

19F MRI Probes with Tunable Switches and Highly Sensitive 19F MRI Nanoprobes

“…9 However, if the number of 19 F is simply multiplied, due to the increase of hydrophobicity the interaction with serum protein or lipid also increases, and from this interaction both molecular motility and the delivery efficiency to the place of interest is hindered. 10 Among these, inhibition of molecular motility results in the shortening of T 2 and in the decrease of sensitivity. Thus, in order to maintain the MRI signal of each 19 F nuclei, a molecular probe design with multiplication of the MR uniform 19 F and free motility of each 19 F nuclei is necessary.…”

Recent Advances in Activatable 19F Magnetic Resonance Imaging Nano‐Probes for the Detection of Biomarkers

“…In addition to 1 H, other NMR-active nuclei such as 3 He, 7 Li, 11 B, 13 C, 15 N, 17 O, 19 F, 23 Na, 31 P, 39 K, and 129 Xe can be used as imaging tools for MRI. [16] Among them, 19 F arguably has attracted the most interest due to its high receptivity (83 % of 1 H), its 100 % isotopic abundance, and its close sensitivity relative to that of 1 H (0.834) (Table 1).…”

“…Recent advances in 19 F MRI molecular probes have revealed the difficulties accompanying their design, particularly with respect to establishing sufficient hydrosolubility (i. e., biocompatibility) while displaying a high amount of 19 F atoms [17] . The use of paramagnetic metal ions gives rise to 19 F‐bearing chelates that modulate the sensitivity of the 19 F MRI signal.…”