Preparation of N(In)-Methyl-6-[(18)F]fluoro- and 5-Hydroxy-7-[(18)F]fluorotryptophans as Candidate PET-Tracers for Pathway-Specific Visualization of Tryptophan Metabolism

Tryptophan (Trp) is an essential proteinogenic amino acid and metabolic precursor for several signaling molecules that has been implicated in many physiological and pathological processes. Since the two main branches of Trp metabolism—serotonin biosynthesis and kynurenine pathway—are differently affected by a variety of neurological and neoplastic diseases, selective visualization of these pathways is of high clinical relevance. However, while positron emission tomography (PET) with existing probes can be used for non-invasive assessment of total Trp metabolism, optimal imaging agents for pathway-specific PET imaging are still lacking. In this work, we describe the preparation of two (18)F-labeled Trp derivatives, N(In)-methyl-6-[(18)F]fluorotryptophan (N(In)-Me-6-[(18)F]FTrp) and 5-hydroxy-7-[(18)F]fluorotryptophan (5-HO-7-[(18)F]FTrp). We also report feasible synthetic routes for the preparation of the hitherto unknown boronate radiolabeling precursors and non-radioactive reference compounds. Under optimized conditions, alcohol-enhanced Cu-mediated radiofluorination of the respective precursors afforded N(In)-Me-6-[(18)F]FTrp and 5-HO-7-[(18)F]FTrp as application-ready solutions in radiochemical yields of 45 ± 7% and 29 ± 4%, respectively. As such, our work provides access to two promising candidate probes for pathway-specific visualization of Trp metabolism in amounts sufficient for their preclinical evaluation.