Biological Evaluation of d-[18F]Fluoroalanine and d-[18F]Fluoroalanine-d3 as Positron Emission Tomography Imaging Tracers for Bacterial Infection.

Abstract

d-Amino acids such as d-alanine are substrates for bacterial peptidoglycan biosynthesis and are selectively taken up by bacteria and not mammalian cells. Consequently, d-amino acid metabolism is an attractive target for antibiotic discovery and the development of bacteria-specific imaging agents. d-Fluoroalanine and the deuterium-labeled analogue fludalanine (MK641) were originally explored as antibiotics by Merck but failed in clinical trials due to unaccepted toxicity. Herein, we synthesized a fluorine-18 labeled d-fluoroalanine, d-3-[¹⁸F]fluoroalanine (d-[¹⁸F]FAla), and its deuterated analogue, d-3-[¹⁸F]fluoroalanine-d₃ (d-[¹⁸F]FAla-d₃), and evaluated their capability to image bacterial infection. Both d-[¹⁸F]FAla and d-[¹⁸F]FAla-d₃ can accumulate up to 0.64-0.78% ID/cc in the infectious area at 15 min postinjection. Despite the reduction of in vivo defluorination not being observed for deuterated ¹⁸F-labeled d-fluoroalanine, these radiolabeled d-alanine analogues were able to differentiate bacterial infection from sterile inflammation in a soft-tissue model of S. aureus infection.