Direct no-carrier-added 18F-labelling of arenes via nucleophilic substitution on aryl(2-thienyl)iodonium salts (2005)

For in vivo imaging of molecular processes via positron emission tomography (PET) radiotracers of high specific activity are demanded. In case of the most commonly used positron emitter fluorine-18, this is only achievable with no-carrier-added [$^{18}$F]fluoride, which implies nucleophilic methods of $^{18}$F-substitution. Whereas electron deficient aromatic groups can be labelled in one step using nocarrier- added [$^{18}$F]fluoride, electron rich $^{18}$F-labelled aromatic molecules are only available by multistep radiosyntheses or carrier-added electrophilic reactions. Here, diaryliodonium salts represent an alternative, since they have been proven as potent precursor for a direct nucleophilic $^{18}$F-introduction into aromatic molecules. Furthermore, as known from non-radioactive studies, the highly electron rich 2-thienyliodonium leaving group leads to a high regioselectivity in nucleophilic substitution reactions. Consequently, a direct nucleophilic no-carrier-added $^{18}$F-labelling of electron rich arenes via aryl-(2-thienyl)iodonium precursors was developed in this work. The applicability of direct nucleophilic $^{18}$F-labelling was examined in a systematic study on eighteen aryl(2-thienyl)iodonium salts. As electron rich precursors the ortho-, meta- and para- ethoxyphenyl(2-thienyl)iodonium bromides, iodides, tosylates and triflates were synthesised. In addition, para-substituted (R = BnO, CH$_{3}$, H, Cl, Br, I) aryl(2-thienyl)iodonium bromides were prepared as precursors with a systematically varying electron density. As first approach, the general reaction conditions of the nucleophilic $^{18}$F-substitution procedure were optimised. The best conditions for direct nucleophilic no-carrier-added $^{18}$F-labelling via aryl(2-thienyl) iodonium salts were found with dimethylformamide as solvent, a reaction temperature of 130 $\\pm$ 3°C and 25 mmol/l as concentration of the precursor. For the effect of bromide, iodide, tosylate and triflate as counter anion on the radiochemical yield (RCY) the following order was obtained: tosylate &lt; iodide &lt; triflate &lt; bromide. However, based on the kinetics a different order was observed for the initial reaction rates with: tosylate &lt; bromide &lt; iodide &lt; triflate. The influence of the substitution pattern in ortho-, meta- and para-methoxyphenyl(2-thienyl)iodonium bromide showed an expected strong orthoeffect, which led with 60 % of 2-[$^{18}$F]fluoroanisole to the highest RCY. Also under no-carrier-added conditions, the 2-thienyl group directed to a regiospecific radiofluorination, thus in all $^{18}$F-substitutions no 2-[$^{18}$F]fluorothiophene, but only the desired [$^{18}$F]fluoroarenes were formed. With the intention of a systematic examination of electronic factors, the kinetics of the $^{18}$F-substitution on substituted aryl(2-thienyl)iodonium bromides were investigated and the determined relative reactivities were compared with the Hammett constants of the corresponding substituents. As result a good linear Hammett correlation and a reaction parameter of $\\rho$ = + 1.16 $\\pm$ 0.2 were obtained. This confirms the S$_{N}$Ar-mechanism and a consistent mechanism over the whole range of investigated substituents. In order to demonstrate the applicability of this method, the $^{18}$F-labelling of two pharmacological relevant molecules was carried out. First, n.c.a. 4-[$^{18}$F]fluorophenol was synthesised via 4-benzyloxyphenyl(2-thienyl)iodonium bromide within 40 min and an overall RCY of 34 to 36 %. Second, a complex AMPA receptor antagonist was $^{18}$F-labelled via iodonium precursors; however only with low RCY of 1.2 to 3.6 %. For comparison, the radioiodine analogue was labelled via a trimethyltin precursor and [$^{131}$I]iodide with a very high RCY of 97 $\\pm$ 2 % within 2 min, thus it was available for preliminary pharmacological evaluation studies. In conclusion, the 2-thienyliodonium leaving group proved as highly effective for direct nucleophilic no-carrier-added 18F-labelling even of nucleophilically non-activated arenes. Concerning the $^{18}$F-labelling of complex molecules, further optimisation, however, is necessary for this method.