Positron emission tomography (PET) is an established imaging modality used for the early detection of tumors and metastases, and plays a critical role in diagnosis, staging, and treatment planning of various malignancies. While the glucose analogue [¹⁸F]FDG is extensively used for tumor imaging, its use for imaging brain and certain solid tumors is limited by high physiological background uptake and poor tumor-to-background contrast. One promising approach is the use of ¹⁸F-labeled amino acids, which exploit upregulated amino acid transport in malignant cells. Among these systems, L-type amino acid transporters (LATs), particularly LAT1, have emerged as attractive molecular targets. LAT1 is highly expressed in tumor tissue but shows limited expression in normal tissues, making it a valuable target for PET imaging.
We developed the LAT1-targeted PET tracer [¹⁸F]-4-fluorohomoleucine ([¹⁸F]FHL), a branched-chain amino acid analogue that is stable in vivo, selectively probes LAT1-mediated amino acid transport, exhibits rapid tumor uptake, and shows minimal bone uptake. In multiple preclinical cancer models, including glioblastoma, prostate cancer, and multiple myeloma, [¹⁸F]FHL demonstrated superior imaging performance relative to [¹⁸F]FDG, characterized by high tumor uptake, excellent contrast, and improved delineation of tumor margins. An early radiosynthetic route to [¹⁸F]FHL relied on electrophilic [¹⁸F]F₂ gas, a limitation that constrained molar activity and restricted production to specialized facilities. To address these challenges, we investigated nucleophilic fluorination using [¹⁸F]fluoride aimed at improving both molar activity and accessibility. Although there have been scattered examples of selective fluorination of tertiary alkyl centers using nucleophilic fluorinating agents in organic and medicinal chemistry, the scope of such processes has remained very limited. Accordingly, we developed a new nucleophilic radiochemical fluorination approach for late-stage incorporation of fluorine-18. This strategy provides a robust and operationally practical route to [¹⁸F]FHL, supporting scalable production, simplified purification, and advancement toward clinical translation of LAT1-targeted PET imaging agents.