A new convenient route to radiofluorinated or radioiodinated aromatic amino acid analogues

Aim: Amino acid transporters (AATs) are proteins that supply cells with amino acids (AAs). Cancer cells, compared to normal ones, often present a rapid growth and a high proliferation rate, supported by increased expression and/or activity of AATs. Radiolabeled AAs that intensively accumulate in tumour cells can provide high contrast SPECT or PET imaging of primary lesions and distant metastases. One of the most upregulated AAT in cancers is the LAT1 system which transports large neutral AAs as branched and aromatic ones. Therefore, a lot of radiolabelled tyrosine analogues have been developed (i.e. O-2-[18F]fluoroethyl-L-tyrosine, [18F]DOPA, [123I]ITIC(OH)). While radioiodinated derivatives of some of these electron-rich arenes are easily available, fluoroaryl analogues are particularly complicated to access by classical nucleophilic substitution with [18F]F-. Based on the ITIC(OH) scaffold, we developed a new synthetic pathway to easily produce radioiodinated or radiofluorinated tyrosine analogues.
Material and methods: A convergent synthetic pathway (Fig. 1) was designed to produce the radioiodinated tracers, reference fluorinated derivatives, and radiofluorinated compounds from common organotin intermediates. The latter were synthesized from iodinated analogues and labelled with [125I]iodide using electrophilic demetallation reaction or converted into iodonium salts for 18F-labelling. The reference fluorinated derivatives were obtained by treatment of the organotin compounds by F-TEDA-PF6. The enantiomeric excess of all produced compounds was assessed by chiral analytic HPLC analyses. For comparison, the corresponding derivatives from the series D were also synthesized.
Results: Our synthetic approach allowed the successful production of non-radioactive iodinated or fluorinated derivatives with high ee (>99%) and with a controlled position of halogenation. While, corresponding radioiodinated structures were easily synthesized using classical electrophilic substitution from organotin intermediates, the access to iodonium salt precursors and radiofluorinated derivatives warranted a lot of investigations to achieve acceptable (radio)chemical yields. Chiral analytical HPLC analyses revealed that no racemisation occurred during radiolabelling with [125I]iodide or [18F]fluoride.
Conclusion: We developed an efficient method to access to radioiodinated or radiofluorinated cyclic tyrosine analogues via organotin and iodonium salt intermediates. This strategy could be extended to a broad range of electron-rich aromatic derivatives.

Fig. 1. Convergent synthetic approach to access to radioiodinated and radiofluorinated cyclic tyrosine analogues via organotin intermediates