Interaction of halogenated tyrosine/phenylalanine-derivatives with Organic Anion Transporter (OAT) 1 in the renal handling of tumor imaging probes

概要

〔目的(Purpose)〕
Halogenated tyrosine/phenylalanine derivatives have been developed for use in tumor imaging and targeted alpha therapy.3-Fluoro-a-methy 1-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 0AT1 (SLC22A6).In the present study, to optimize the halogenated compounds that exhibit low interaction with 0AT1 and high specificity for LATl-mediated transport, we investigated the structural requirements of FAMT for interaction with 0AT1.

〔方法ならびに成績(Methods/Results)〕
We investigated the structural reduirenients of FAMT essential for interaction with OATL 0AT1 transported FAMT with a of 171.9 uM.In structure-activity relationship analyses, removal of either the 3~halogen or 4-hydroxyl group from FAMT or its structural analog 3-iodo-alpha-methyl-L-tyrosine greatly decreased the interaction with OATl, reducing the 14C-p-aminohyppurate uptake inhibition and the efflux induction.By contrast, the α-methyl group, which is essential for LATl-specificity, contributed to a lesser degree.In fluorinated tyrosine derivatives, fluorine at any position was accepted by 0AT1 when there was a hydroxyl group at the orth-otposition,whereas luorine 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 OAT 1-mediated trans-epilhelial organic anion excretion.LATl-specific 2- fluoro-a-methyl-tyrosine, which had lower affinity for 0AT1, exhibited lower renal accumulation (p =0.0142) and higher tumor uptake (p = 0.0192) compared with FAMT.

〔総括(Conclusion)〕
We revealed the structural characteristics of halogenated tyrosine derivatives used as tumor­imaging probes essential for interaction with the organic anion transporter responsible for their renal accumulation.We have confirmed that such interactions are important for renal handling and tumor uptake.The critical contribution of hydroxyl and halogen groups and their positions, as welI as the role of a- niethyl group found in the present study would provide a basis to design tumor specific compounds that can avoid renal accumulation for tumor imaging and targeted alpha therapy.