Radiosynthesis of 3-[¹⁸F]fluoropropanesulfonamides derived from aliphatic and aromatic amines

Objectives:

Facing the ample palette of prosthetic groups available for the introduction of radiofluorine into pharmacologically relevant molecules, the careful selection of the appropriate labelling agent often reveals critical for tracer development as it can influence target binding and/or stability in vivo. Labelling based on the formation of carboxylic acid amides often results in metabolic instability due to hydrolytic cleavage. As an alternative to acyl-based prosthetic groups the 3-[¹⁸F]fluoropropanesulfonyl group introduced by Li et al. attracted our interest [1]. Therefore, we established and optimised the preparation of 3-[¹⁸F]fluoropropanesulfonyl chloride in our lab and studied its reaction with various aliphatic and aromatic amines.
Methods:
To obtain 3-[¹⁸F]fluoropropanesulfonyl chloride ([¹⁸F]4) we followed the route described in [1] that includes conversion of intermediary 3-[¹⁸F]fluoropropyl thiocyanate ([¹⁸F]3) with chlorine leading to the desired sulfonyl chloride (Figure 1). As the preparation of [¹⁸F]3 from the corresponding tosyl precursor 1 proceeded with only moderate labelling yields, the nosylate 2 was synthesised by two different pathways both starting from 3-bromopropanol. The syntheses of the non-radioactive sulfonamides as reference compounds resembled those of the radiotracers with the oxidation of 3 to 4 as the key step. This was realised by employing a solution of chlorine in water using acetic acid as organic co-solvent. The resulting sulfonyl chloride 4 was reacted with various aliphatic and aromatic amines. Due to the fact that 3 and 4 show an almost identical chromatographic behaviour on silica gel
as observed by TLC, a radio-HPLC method had to be developed that allowed to prove the identity of [¹⁸F]4 but prevented its hydrolysis on the column. The synthesis of the final radioactive sulfonamides was done by reacting
[¹⁸F]4 with different primary and secondary aliphatic amines as well as various aniline derivatives in dichloromethane at room temperature both in the absence and presence of triethylamine (TEA) and/or 4-
dimethylaminopyridine (DMAP) as reaction enhancing mediators. The results were evaluated by radio-TLC and radio-HPLC.
Results:
The nosyl precursor 2 accounted for high labelling yields of 78-85% (n=11) in the first step of the radiosynthesis. A concentration of 2.5 to 3.0 mg/mL and a reaction time of 10 min in acetonitrile (approx. 0.4 mL) at reflux were found to be optimal for the radiofluorination of 2. For the conversion of [¹⁸F]3 into the corresponding sulfonyl chloride the repetitive treatment of this intermediate adsorbed at a C₁₈ matrix with an aqueous solution of chlorine and subsequent desorption with dichloromethane led to [¹⁸F]4 of high radiochemical purity ranging from 85 to 95%. The reaction of [¹⁸F]4 with primary amines always resulted in high yields of radioactive sulfonamides (75 to 85%) that did not improve upon addition of TEA or DMAP. In contrast, the conversion of [¹⁸F]4 with various anilines was low (<10%) but could be significantly increased in the presence of TEA or DMAP resulting in yields of 55 to 65%.
Conclusions:
The structural optimisation of the sulfonate precursor together with optimised reaction conditions for the radiosynthesis of 3-[¹⁸F]fluoropropanesulfonyl chloride ([¹⁸F]4) enabled the preparation of 3-[¹⁸F]fluoropropanesulfonamides derived from various aliphatic and aromatic amines. This will allow the preparation of ¹⁸F-labelled sulfonamides of pharmacologically interesting amino-functionalised compounds.
References:
[1] Li et al. (2008) J. Label. Compd. Radiopharm. 51, 23-27