A LAT1-selective PET tracer, 5-[¹⁸F]F-αMe-3BPA, as a companion to its structurally matched ¹⁰B analog in boron...

This study aimed to develop and evaluate 5-[¹⁸F]F-αMe-3BPA, a novel PET probe designed as a theranostic partner for 5F-αMe-3[¹⁰B]BPA in Boron Neutron Capture Therapy (BNCT). The goal was to address limitations of the clinically used BPA/[¹⁸F]FBPA pair, including poor water solubility, limited LAT1 specificity, and suboptimal diagnostic performance, thereby improving tumor-selective drug delivery and enabling accurate prediction of therapeutic biodistribution through structure-matched PET/BNCT.

LAT1 dependency was tested in vitro using cancer cell lines with differential LAT1 expression. In vivo biodistribution of both therapeutic agents and their ¹⁸F-labeled analogs were assessed in xenograft mouse models. Radiosynthesis of 5-[¹⁸F]F-αMe-3BPA was achieved via copper-catalyzed nucleophilic radiofluorination. PET/CT imaging compared tumor visualization with [¹⁸F]FBPA. Co-injection studies (5-[¹⁸F]F-αMe-3BPA/5F-αMe-3BPA and [¹⁸F]FBPA/BPA) quantitatively evaluated concordance between ¹⁸F radioactivity and boron concentrations across tissues.

5F-αMe-3BPA uptake in cancer cells was strictly LAT1-dependent. In LAT1-high T3M-4 xenografts, its tumor-to-muscle boron ratio (22) far exceeded BPA (3.4). 5-[¹⁸F]F-αMe-3BPA was synthesized successfully and achieved a tumor-to-muscle ratio of 29 versus 5.3 for [¹⁸F]FBPA. PET imaging showed clear, high-contrast visualization of T3M-4 tumors, with co-injection confirming strong concordance between PET probe and therapeutic agent biodistribution.

The 5-[¹⁸F]F-αMe-3BPA/5F-αMe-3[¹⁰B]BPA theranostic pair demonstrates high LAT1 specificity, low normal tissue uptake, and strong pharmacokinetic alignment, enabling accurate prediction of therapeutic boron delivery for BNCT. Furthermore, 5-[¹⁸F]F-αMe-3BPA shows promise as a dedicated LAT1 imaging probe for advancing LAT1-targeted therapies.