Radiosynthesis and Preclinical Evaluation of Enantiopure (R)-[18F]Fluorolactate for PET Imaging of Metabolic Processes.

Abstract

L-Lactate is a key substrate in energy metabolism and a potential biomarker for cancer and metabolic disorders. We developed an enantiomerically pure positron emission tomography (PET) tracer, (R)-[¹⁸F]fluorolactate, to mimic natural L-lactate. (R)-[¹⁸F]Fluorolactate was synthesized via nucleophilic ring-opening of benzyl (S)-oxirane-2-carboxylate, optimized to yield >91% radiochemical purity, > 95% enantiomeric excess, pH 6, and >5.56 GBq/μmol molar activity. PET/computed tomography (CT) imaging, biodistribution, autoradiography, and stability analyses were conducted in fasted and nonfasted rats and in mice bearing subcutaneous Lewis lung carcinoma (LLC) tumors. In rats, tracer uptake was highest in the kidneys and liver, with fasting further increasing renal and hepatic uptake. In mice, (R)-[¹⁸F]fluorolactate accumulated in tumors. The monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 significantly reduced tracer uptake in normal tissues and LLC tumors, and increased renal excretion, confirming MCT1-mediated transport. More than 80% and 90% of the tracer remained intact in plasma at 70 min postinjection in rats and tumor-bearing mice, respectively. In silico structural analyses supported the experimental findings. (R)-[¹⁸F]Fluorolactate is a metabolically stable, MCT1-sensitive PET tracer suitable for noninvasive assessment of lactate transport and metabolism and shows promise for imaging MCT1-dependent lactate transport in cancer.