Synthesis and Preclinical Evaluation of 6-[¹⁸F]Fluorine-α-methyl-l-tryptophan, a Novel PET Tracer for Measuring Tryptophan Uptake

The positron emission tomography (PET) radioligand α-[¹¹C]methyl-l-tryptophan ([¹¹C]AMT) has been used to assess tryptophan metabolism in cancer, epilepsy, migraine, and autism. Despite its extensive application, the utility of this tracer is currently hampered by the short half-life of the radionuclide used for its labeling (¹¹C, t_1/2 = 20.4 min). We herein report the design, synthesis, radiolabeling, and initial in vivo evaluation of a fluorine-18 (¹⁸F, t_1/2 = 109.7 min) labeled analogue that is fluorinated in the 6-position of the aromatic ring ([¹⁸F]6-F-AMTr). In a head-to-head comparison between [¹⁸F]6-F-AMTr and [¹¹C]AMT in mice using PET, peak brain radioactivity, regional brain distribution, and kinetic profiles were similar between the two tracers. [¹⁸F]6-F-AMTr was however not a substrate for IDO1 or TPH as determined in in vitro enzymatic assays. The brain uptake of the tracer is thus more likely related to LAT1 transport over the blood-brain barrier than metabolism along the serotonin or kynurenine pathways.