Abstract

Halogenated tyrosine/phenylalanine derivatives have been developed for use in tumor imaging and targeted alpha therapy. 3-Fluoro-α-methyl-l-tyrosine (FAMT), targeting amino acid transporter LAT1 (SLC7A5), is a cancer-specific positron-emission-tomography probe yet exhibits high renal accumulation supposed to be mediated by organic anion transporter OAT1 (SLC22A6). In the present study, we investigated the structural requirements of FAMT essential for interaction with OAT1. OAT1 transported FAMT with a K_m of 171.9 μM. In structure-activity relationship analyses, removal of either the 3-halogen or 4-hydroxyl group from FAMT or its structural analog 3-iodo-α-methyl-l-tyrosine greatly decreased the interaction with OAT1, reducing the ¹⁴C-p-aminohyppurate uptake inhibition and the efflux induction. By contrast, the α-methyl group, which is essential for LAT1-specificity, contributed to a lesser degree. In fluorinated tyrosine derivatives, fluorine at any position was accepted by OAT1 when there was a hydroxyl group at the ortho-position, whereas ortho-fluorine was less interactive when a hydroxyl group was at meta- or para-position. The replacement of the ortho-fluorine with a bulky iodine atom greatly increased the interaction. In in vivo studies, probenecid decreased the renal accumulation (p < 0.001) and urinary excretion (p = 0.0012) of FAMT, whereas the plasma concentration was increased, suggesting the involvement of OAT1-mediated trans-epithelial organic anion excretion. LAT1-specific 2-fluoro-α-methyl-tyrosine, which had lower affinity for OAT1, exhibited lower renal accumulation (p = 0.0142) and higher tumor uptake (p = 0.0192) compared with FAMT. These results would provide a basis to design tumor specific compounds that can avoid renal accumulation for tumor imaging and targeted alpha therapy.

Significance Statement We revealed the structural characteristics of halogenated tyrosine derivatives used as tumor-imaging probes essential for interaction with the organic anion transporter responsible for their renal accumulation, confirmed that such interactions are important for renal handling and tumor uptake. The critical contribution of hydroxyl and halogen groups and their positions, as well as the role of a-methyl group found in the present study may facilitate the development of tumor-specific compounds while avoiding renal accumulation for use in tumor imaging and targeted-alpha-therapy.