Single-step Radiosyntheses of '18F-Labeled Click Synthons' from Azide-functionalized Diaryliodonium Salts

Abstract

Positron emission tomography (PET) is an increasingly important biomedical imaging technique that relies on the development of radiotracers labeled with positron-emitters to achieve biochemical specificity. Fluorine-18 (t_1/2 = 109.7 min) is an attractive positron-emitting radiolabel for organic radiotracers, primarily because of its longer half-life and greater availability relative to those for the main alternative, carbon-11 (t_1/2 = 20.4 min). Rapid simple methods are sought for labeling prospective PET radiotracers with fluorine-18 from cyclotron-produced aqueous [¹⁸F]fluoride ion, which must often be converted first into a suitably reactive labeling synthon for use in a subsequent labelling reaction. Use of ¹⁸F-labeled synthons in 'click chemistry' attracts increasing attention for labeling PE Tradiotracers. Here we describe rapid single-step radiosyntheses of azido- or azidomethyl-bearing [¹⁸F]fluoroarenes from the reactions of diaryliodonium salts with no-carrier-added [¹⁸F]fluoride ion within a microfluidic apparatus to provide previously poorly accessible ¹⁸F-labeled click synthons in radiochemical yields of 15% for [¹⁸F]4-fluorophenyl azide and about 40% for each of the [¹⁸F](azidomethyl)-fluorobenzenes. The radiosyntheses of the latter synthons was possible under 'wet conditions', so obviating the need to dry the cyclotron-produced [¹⁸F]fluoride ion and greatly enhancing the practicality of the method.

Keywords: Click chemistry; Hypervalent compounds; Imaging agents; Isotopic labeling; Radiochemistry.

Figure 1

Previously reported [¹⁸F]fluoroaryl azides.

Figure 2

Radiosynthesis of [¹⁸F]fluoroarenes from diaryliodonium salts.

Figure 3

mCPBA-mediated one-pot syntheses of azide–bearing diaryliodonium tosylates.

Figure 4

Radio-HPLC chromatograms for the analysis of radioactive products from the radiofluorination of 11 in the temperature range 120–200 °C.

Scheme 1

One-pot syntheses of diaryliodonium tosylates from iodoaryl azides and subsequent conversion into their corresponding halides. General reaction conditions: i) iodoaryl azide (1 equiv.), mCPBA (1.1 equiv.); ii) pTsOH·H₂O (1.1 equiv.), iii) CHCl₃ and ArH (excess, 5–10 fold); iv) MX = NH₄Cl (9–11, 14), KBr (12) or KI (13).