An efficient route to obtain (radio)fluorinated or (radio)iodinated 1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (TIC(OH)) analogues as potential radiotracers for imaging of solid tumours

Introduction:

The use of radiolabelled amino acids (AAs) can provide high contrast SPECT/PET imaging of solid tumours. Among them, radiohalogenated tyrosine analogues ([123I]IMT, [18F]FDOPA, [123I]8-iodo-L-TIC(OH), etc) were developed mainly for imaging of neuroendocrine, prostatic and brain tumours. While radioiodinated derivatives are easily available via electrophilic aromatic substitutions with radioactive I+, radiofluorinated tyrosine analogues are difficult to obtain. Indeed, direct radiofluorination of electron-rich aromatic structures from [18F]F- remains a challenge as evidenced by the number of emerging methods recently published. The progresses reported for the radiosynthesis of the [18F]FDOPA illustrate the 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.

Materials and 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 minutes 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 (> 1.5-2.9 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 catalyst and nucleophilic [18F]F- at 110 °C for 10 minutes 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%), molar activities (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) compounds from common organotin intermediates. In vitro studies on human cancer cell lines are ongoing to evaluate the potential of these radioligands to target AAs transporters.