Deuterium- and Fluorine-18-Labeled Glutaminea PET Imaging Agent with Enhanced In Vivo Stability.

Deuterium and fluorine-18 dual-isotope-labeled fluoroglutamine, (2S,4R)-[4-(18)F-3,3,4-d (3)]-fluoroglutamine (4-[(18)F]-FGln-d (3)), was designed, synthesized, and biologically evaluated for its potential as a novel glutamine metabolic imaging agent with improved in vivo stability. The tetradeuterated homoserine 11 intermediate was first synthesized via a six-step synthetic pathway, including a chiral HPLC separation process. Next, (2S,4S)-tosylate precursor 14 was prepared following the reference-reported method, and 4-[(18)F]-FGln-d (3) was successfully prepared using a semiautomated production process. After that, a head-to-head comparison of 4-[(18)F]-FGln-d (3) with its parent compound 4-[(18)F]-FGln including in vitro cell uptake and in vivo murine animal imaging studies illustrated that the new tracer 4-[(18)F]-FGln-d (3) has a similar cell uptake manner and comparable tumor uptake and tumor-to-muscle ratio as 4-[(18)F]-FGln, but moderately decreased radioactivity bone uptake at 120 min postinjection. Overall, the preliminary data from this research indicate the better in vivo stability of 4-[(18)F]-FGln-d (3) compared with its counterpart 4-[(18)F]-FGln, which warrants further investigation of this radiotracer as the new PET imaging agent with enhanced stability for probing the glutamine metabolism in vivo.