Organotin derivatives as versatile precursors for the radioiodination and radiofluorination of 1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (TIC(OH)) analogues

Objective: Organotin compounds are well known as efficient precursors for reliable radioiodination of aromatic derivatives, with high molar activities, via electrophilic aromatic substitution reaction. They can be easily prepared from corresponding halogenated derivatives using metalation or palladium-catalyzed reactions. In the last years, organotin derivatives, together with boronic acid or ester precursors, were also successfully applied to the direct radiolabelling of electron-rich aromatic structures from [18F]F- via Cu-mediated radiofluorination. As evidenced with the progresses reported for the radiosynthesis of the [18F]FDOPA for example, these major developments in the fluorine-18 radiochemistry field created new opportunities to produce radiofluorinated arenes that could not be routinely accessed even a few years ago. Surprisingly, the [123I]8-iodo-L-TIC(OH), a promising radiotracer for SPECT imaging of prostatic tumours, did not benefit from these methodological advances and no corresponding radiofluorinated derivatives, which could allow the use of the TIC(OH) scaffold to PET imaging, were reported so far.

Methods: A convergent synthetic route was developed to produce radioiodinated [125I]iodo-L-TIC(OH), and radiofluorinated [18F]fluoro-L-TIC(OH) tracers from common organotin intermediates, synthesized from iodinated analogues via palladium catalyzed I/SnMe3 exchange. The [125I]iodo-L-TIC(OH) radiotracers were obtained by electrophilic radioiododestannylation with [125I]I+, while the radiofluorinated analogues [18F]fluoro-L-TIC(OH) were produced from the organotin precursors by a copper-mediated aromatic radiofluorination using nucleophilic [18F]F-. For control of the purity, molar activity and enantiomeric excess, corresponding non-radiolabelled iodinated and fluorinated derivatives from the L and D series were synthesized.

Results: Organotin compounds were radiolabelled using no-carrier-added [125I]NaI in the presence of Chloramine-T as mild oxidative agent at room temperature for 5 min with excellent labelling efficiencies (> 95%). After a two-step deprotection sequence and semipreparative RP-HPLC purification, [125I]iodo-L-TIC(OH) compounds were isolated with good radiochemical yields (RCY = 51-78%), high radiochemical purities (RCP, > 98%), molar activities (MA > 1.5 GBq/µmol) and enantiomeric excess (e.e. > 99%). [18F]fluoro-L-TIC(OH) derivatives were obtained by radiofluorination of organotin compounds in presence of tetrakis(pyridine)copper(II) triflate and nucleophilic [18F]F- at 110 °C for 10 min with high labelling efficiencies (54-92%). After purification by C18 solid phase extraction, deprotection under acidic conditions and semipreparative RP-HPLC purification, [18F]fluoro-L-TIC(OH) radiotracers were produced with good RCY (23-37% d.c.), high RCP (> 99%), MA (20-107 GBq/µmol) and e.e. (> 99%).

Conclusion: A short and efficient synthetic pathway was developed to easily produce [125I]iodo-L-TIC(OH) and [18F]fluoro-L-TIC(OH) analogues from common organotin intermediates. Such radiofluorination process could be easily implemented on radiopharmacy automatic synthesis modules and could pave the way to the development of novel radiopharmaceuticals containing the TIC(OH) core.

Acknowledgments : This work was partially funded by the Cancéropôle Lyon Auvergne Rhône Alpes (CLARA), the Auvergne Rhône Alpes Region, the ARTP (Association pour la Recherche sur les Tumeurs de la Prostate), and the Fondation de la Maison de la Chimie.