RT Journal Article SR Electronic T1 18F-Branched-Chain Amino Acids: Structure–Activity Relationships and PET Imaging Potential JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1003 OP 1009 DO 10.2967/jnumed.118.220483 VO 60 IS 7 A1 Matthew B. Nodwell A1 Hua Yang A1 Helen Merkens A1 Noeen Malik A1 Milena Čolović A1 Björn Wagner A1 Rainer E. Martin A1 François Bénard A1 Paul Schaffer A1 Robert Britton YR 2019 UL http://jnm.snmjournals.org/content/60/7/1003.abstract AB The large, neutral L-type amino acid transporters (LAT1–LAT4) are sodium-independent transporters that are widely distributed throughout the body. LAT expression levels are increased in many types of cancer, and their expression increases as cancers progress, leading to high expression levels in high-grade tumors and metastases. Because of the key role and overexpression of LAT in many types of cancer, radiolabeled LAT substrates are promising candidates for nuclear imaging of malignancies that are not well revealed by conventional radiotracers. The goal of this study was to examine the structure–activity relationships of a series of 18F-labeled amino acids that were predicted to be substrates of the LAT transport system. Methods: Using a photocatalytic radical fluorination, we prepared a series of 11 fluorinated branched-chain amino acids and evaluated them and their nonfluorinated parents in a cell-based LAT affinity assay. We radiofluorinated selected branched-chain amino acids via the same radical fluorination reaction and evaluated tumor uptake in U-87 glioma xenograft–bearing mice. Results: Structure–activity relationship trends observed in a LAT affinity assay were maintained in further in vitro studies, as well as in vivo using a U-87 xenograft model. LAT1 uptake was tolerant of fluorinated amino acid stereochemistry and chain length. PET imaging and biodistribution studies showed that the tracer (S)-5-18F-fluorohomoleucine had rapid tumor uptake, favorable in vivo kinetics, and good stability. Conclusion: By using an in vitro affinity assay, we could predict LAT-mediated cancer cell uptake in a panel of fluorinated amino acids. These predictions were consistent when applied to different cell lines and murine tumor models, and several new tracers may be suitable for further development as oncologic PET imaging agents.