[¹⁸F]Fluoroacetyl chloride, a new reagent for [¹⁸F]fluoroacylation of amino and hydroxyl groups

Abstract

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Objectives: The [¹⁸F]fluoroacetyl ([¹⁸F]FAc) moiety is an useful prosthetic group for introducing F-18 into biomarkers for PET imaging. For labeling complex biomarkers having sensitive functional groups with the [¹⁸F]FAc moiety under mild conditions, we have prepared [¹⁸F]fluoroacetyl chloride ([¹⁸F]FAcCl) for the first time. The utilization of this new reagent in [¹⁸F]fluoroacylations of amino and hydroxyl groups in model compounds is demonstrated.

Methods: Reaction of ethyl bromoacetate or ethyl tosyloxyacetate with no-carrier-added [¹⁸F]fluoride ion in the presence of Kryptofix 2.2.2 in MeCN followed by hydrolysis with 0.5M KOH yielded [¹⁸F]fluoroacetic acid, potassium salt (radiochemical yields: 95% and 89% from the bromo- and tosyloxy derivatives, respectively, as determined by radioTLC). Subsequent reaction of the [¹⁸F]fluoroacetate salt with phthaloyl dichloride generated [¹⁸F]FAcCl in the gas-phase with a radiochemical yield of 45 ± 10% (n=18). [¹⁸F]FAcCl was conveniently bubbled, with a stream of N₂, into an ice-cold solution of aniline (1), 2-phenylethanol (2), trans-4-tert-butylcyclohexanol (3) or trans-2-phenylcyclohexanol (4) in CH₂Cl₂ containing Et₃N or DMAP as a catalyst to provide the corresponding [¹⁸F]FAc derivatives. Pure [¹⁸F]fluoroacetylated products were then obtained by semi-preparative HPLC purification.

Results: Chemically and radiochemically pure [¹⁸F]FAc derivatives of 1, 2, 3 and 4 were obtained in 21 ± 6% (n = 9), 13 ± 6% (n=3), 16 ± 11% (n=3) and 6 ± 3% (n=3) radiochemical yields, respectively with an average specific activity of 3,060 Ci/mmol (EOS).

Conclusions: The feasibility of the preparation of [¹⁸F]FAcCl and its use in labeling of amino and hydroxyl groups under mild conditions have been demonstrated. Extension of this technique to the synthesis of complex PET biomarkers like rapamycin is currently underway.

Research Support (if any): Supported by the Department of Energy Grant.