Use of 3-[¹⁸F]fluoropropanesulfonyl chloride as a prosthetic agent for the radiolabelling of amines: Investigation of precursor molecules, labelling conditions and enzymatic stability of the corresponding sulfonamides

Abstract

Summary3-[18F]Fluoropropanesulfonyl chloride, a recently proposed prosthetic agent for fluorine-18 labelling, was prepared in a two-step radiosynthesis via 3-[18F]fluoropropyl thiocyanate as an intermediate. Two benzenesulfonate-based radiolabelling precursors were prepared by various routes. Comparing the reactivities of 3-thiocyanatopropyl nosylate and the corresponding tosylate towards [18F]fluoride the former proved to be superior accounting for labelling yields of up to 85%. Conditions for a reliable transformation of 3-[18F]fluoropropyl thiocyanate to the corresponding sulfonyl chloride with the potential for automation have been identified. The reaction of 3-[18F]fluoropropanesulfonyl chloride with eight different aliphatic and aromatic amines was investigated and the identity of the resulting 18F-labelled sulfonamides was confirmed chromatographically by comparison with their nonradioactive counterparts. Even for weakly nucleophilic amines such as 4-nitroaniline the desired radiolabelled sulfonamides were accessible in satisfactory yields owing to systematic variation of the reaction conditions. With respect to the application of the 18F-fluoropropansulfonyl group to the labelling of compounds relevant as imaging agents for positron emission tomography (PET), the stability of N-(4-fluorophenyl)-3-fluoropropanesulfonamide against degradation catalysed by carboxylesterase was investigated and compared to that of the analogous fluoroacetamide.

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

“…These groups are referred to as secondary labeling precursors or prosthetic groups [148,169,170] . A large number of these 18 F-labeled intermediates have been prepared and investigated, such as amines, alcohols, aldehydes, ketones, carboxylic acids, esters, and halides [148] .…”

“…High metabolic stability of the ether bond is expected because negligible defluorination was observed [178] . By contrast, [ 18 F]fl uoroacetamides have proven to be metabolically unstable due to hydrolytic cleavage [169] . Thus, high-affinity and selective radiotracers for the VAChT [179] and the GABA A receptor [180] , respectively, are not suitable for in vivo imaging because metabolites that cross the BBB are generated.…”

“…These groups are referred to as secondary labeling precursors or prosthetic groups [148,169,170] . A large number of these 18 F-labeled intermediates have been prepared…”

“…Thus, it can be used for the radiolabeling of water-soluble biomolecules [148,[171][172][173][174][175] . Generally, careful selection of prosthetic groups is critical for radiotracer development as they often exert great infl uence on target binding and/or in vivo stability [169] .A further path to 18 F-labeled radiotracers is starting the labeling of a pre-prepared substance (reactive precursor) in a fi rst step and its chemical transformation in a subsequent reaction into the final product. This is demonstrated by means of a ring closure reaction (McMurry coupling, Fig.…”

“…carboxylesterase [169] . In such cases, the use of [ 18 F]fluoropropane sulfonamides Peter Brust, et al Development of 18 F-labeled radiotracers for neuroreceptor imaging with PET 789 can be recommended because of their stability against carboxylesterase-mediated hydrolysis [169] . …”