The high lipophilicity and the strong electron-withdrawing effect of the trifluoromethyl group make aryltrifluoromethyl derivatives a desirable moiety in the development of novel pharmaceuticals. Three recent examples are the serotonin agonst, and the nonpeptidal antagonists and of substance P. It has been demonstrated in comse cases that biological activity does not significantly change upon replacing one hydrogen atom with a fluorine atom. Therefore, development of an efficient way of labeling drugs containing both a trifluoromethyl group and a fluorine-18 directly substituted on an aromatic ring may be an interesting method for the labeling of various radiopharmaceuticals. In order for this reaction to be effective, the aromatic ring must be activated to nucleophilic attack. This has been well demonstrated by successful radiolabeling of nitroacetophenone and nitrobenzonitrile. To extend this approach we have evaluated 18F radiolabeling of aromatic nitro compounds that contain a trifluoromethyl substituent. Reaction of resolubilized (18F)fluoride ion with 2-nitro-a,a,a-trifluorotoluene (microwave, 2 minutes) gave 2-(18F)fluoro-a,a,a-trifluorotoluene in 80% radiochemical yield. No isotopic exchange was observed by HPLC. The yield was less impressive for the para position, and in this case because of the lower reactivity of the nitro group we also abserved 1-4% isotopic exchange. As with many other electron-withdrawing groups, the nitro at the meta position did not react at all. Addition of another electron-withdrawing group at the meta position activated the nitro group and the yield increased to 80%, while no isotopic exchange was observed. Encouraged by these results, we turned our attention toward the synthesis of the substance P antagonist. Reaction of 2-chloro-5-nitrobenzaldehyde with dibromofluoromethane in the presence of copper gave the 5-nitro-2-trifluoromethyl benzaldehyde in 70% yield. The latter was reacted with K18F/kryptofix in a conventional microwave for 2.5 min to give the desired 5-(18F)fluoro-2-tribluoromethyl benzaldehyde in 75% radiochemical yield, and the compound was readily purified on a C18 Sep Pak. Reductive alkylation with sec-butylamine and NaCNBH3 produced a compound in 65% radiochemical yield. We attempted to incorporate the 18F at the final step by radiolabeling the imine. However, this gave a low yield of 20%, an observation similar to those obtained for the simple toluenes. In summary, we have evaluated the ability of the aryltrifluoromethyl derivatives to mediate (18F)fluoro-for-nitro exchange in simple trifluorotoluene and have synthesized a model compound that has potential as a novel radiopharmaceutical.

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Yue, Xuyi; Dhavale, Dhruva D; Li, Junfeng et al. (2018) Design, synthesis, and in vitro evaluation of quinolinyl analogues for ?-synuclein aggregation. Bioorg Med Chem Lett 28:1011-1019
Ohlemacher, Shannon I; Giblin, Daryl E; d'Avignon, D André et al. (2017) Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria. J Clin Invest 127:4018-4030
Lin, Xiaobo; Racette, Susan B; Ma, Lina et al. (2017) Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima-Media Thickness in Humans. Arterioscler Thromb Vasc Biol 37:2364-2369
Ovod, Vitaliy; Ramsey, Kara N; Mawuenyega, Kwasi G et al. (2017) Amyloid ? concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement 13:841-849
Cade, W Todd; Levy, Philip T; Tinius, Rachel A et al. (2017) Markers of maternal and infant metabolism are associated with ventricular dysfunction in infants of obese women with type 2 diabetes. Pediatr Res 82:768-775
Lucey, Brendan P; Mawuenyega, Kwasi G; Patterson, Bruce W et al. (2017) Associations Between ?-Amyloid Kinetics and the ?-Amyloid Diurnal Pattern in the Central Nervous System. JAMA Neurol 74:207-215
Wei, Xiaochao; Song, Haowei; Yin, Li et al. (2016) Fatty acid synthesis configures the plasma membrane for inflammation in diabetes. Nature 539:294-298
Shields-Cutler, Robin R; Crowley, Jan R; Miller, Connelly D et al. (2016) Human Metabolome-derived Cofactors Are Required for the Antibacterial Activity of Siderocalin in Urine. J Biol Chem 291:25901-25910
Mertins, Philipp; Mani, D R; Ruggles, Kelly V et al. (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534:55-62
Murata, Takahiro; Dietrich, Hans H; Horiuchi, Tetsuyoshi et al. (2016) Mechanisms of magnesium-induced vasodilation in cerebral penetrating arterioles. Neurosci Res 107:57-62

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