Unravelling the role of L- and D- alanine in prostate cancer: a Positron Emission Tomography study in a genetic mouse model.

[INTRODUCTION] Cancer cells often exhibit aberrant cellular metabolism, with a common characteristic being their reliance on anaerobic glucose utilization. Prostate cancer (PC), however, displays unique metabolic profiles that extend beyond glycolysis, notably incorporating amino acid metabolism. This divergence in metabolic patterns opens potential avenues for targeted therapeutic strategies using D-amino acids. In this work, we investigated the biodistribution and tumour accumulation of D- and L-[methyl-C]alanine using positron emission tomography (PET) imaging in a genetic mouse model of prostate cancer.

[METHODS] D- and L-[methyl-C]alanine were synthesized according to established protocols. Conditional PTEN knockout mice (n = 6) were used as a model for prostate cancer. Dynamic PET-CT scans were performed for 60 min immediately following intravenous administration of the radiolabelled amino acids at the ages of 4 and 7 months. PET images were reconstructed, and volumes of interest (VOIs) were delineated in major organs, including the prostate and bladder. Dynamic time-activity curves (TACs) were analysed in terms of Standardized Uptake Values (SUV). After imaging, samples of the reproductive system were collected for static PET-CT imaging and subsequent histological analysis.

[RESULTS AND DISCUSSION] L- and D-[methyl-C]alanine were synthesized with good radiochemical yields and high enantiomeric excess using enantioselective alkylation with [C]methyl iodide in the presence of a chiral phase transfer catalysts. PET imaging of a genetic faithful mouse model of prostate cancer demonstrated that D-[methyl-C]alanine exhibited faster blood clearance, higher age-dependent kidney retention, and greater prostate lesion uptake at 7 months compared to L-[methyl-C]alanine. Histological analysis confirmed malignant lesions in the prostate of PTEN knockout mice, corroborating the PET imaging findings.

[CONCLUSIONS] Our study offers valuable insights into the metabolic landscape of prostate cancer using a genetic mouse model that closely mimics human disease pathogenesis. The significantly greater accumulation of D-[methyl-C]alanine compared to its L-enantiomer underscores the potential of D-amino acids as biomarkers, and their potential use to interfere with cancer cell metabolism.