Oral Intake of Deuterated Choline at Clinical Dose for Metabolic Imaging of Brain Tumors

Abstract Accurate characterization and imaging of brain tumors are essential for effective treatment planning and monitoring. While MRI is widely used because of its high sensitivity for detecting lesions, the range of available types of MR image contrast does not offer high specificity for tumors. Deuterium metabolic imaging (DMI), which combines 2H magnetic resonance spectroscopic imaging (MRSI) with administration of deuterium-labeled substrates, is a relatively new imaging approach that could provide unique, complementary information to anatomical MRI. Preclinical studies have demonstrated the feasibility of DMI with intravenous (IV) administration of deuterated choline (2H9-Cho) for tumor characterization; however, they were performed at doses that exceeded severalfold the daily recommended Cho intake. Here, we investigated the feasibility of oral (PO) administration of 2H9-Cho with a dose set at the recommended upper limit for daily use in humans. DMI was performed in rats with orthotopic glioblastoma tumors following a single, high-dose IV bolus (1 × 285 mg/kg) or low-dose PO administration over three consecutive days (3 × 50 mg/kg). Despite a lower cumulative dose, PO administration resulted in comparable total deuterated Cho (2H9-tCho) concentrations in the tumor, and tumor-to-brain image contrast relative to IV administration. Additionally, 2H and 2D 1H-14N HSQC NMR analyses on excised tumor tissue revealed differences in metabolite contributions to the in vivo 2H9-tCho peak. PO administration led to increased contributions from Cho-derived molecules that were products of tumor metabolism, than during IV infusion of 2H9-Cho. These findings suggest that repeated low-dose PO 2H9- Cho administration can generate high, image contrast between tumor and normal brain, that is predominantly generated by tumor metabolism instead of merely Cho uptake. These results can advance the clinical translation of tCho-DMI as a noninvasive imaging tool for brain tumor characterization by demonstrating the feasibility of an oral intake approach using a clinically relevant dose. Given that Cho is already a widely used and well-tolerated nutritional supplement, oral Cho administration offers a practical, noninvasive alternative to IV infusion that could be conducted alongside regular MRI. Competing Interest Statement The authors have declared no competing interest. List of Abbreviations - DMI - Deuterium metabolic imaging - MRSI - Magnetic resonance spectroscopic imaging - tCho - total choline (= choline, phosphocholine, glycerophosphocholine, and betaine); tCho’total choline excluding betaine - HSQC - Heteronuclear single quantum coherence - Cho - Choline - PC - Phosphocholine - GPC - Glycerophosphocholine, - GBM - Glioblastoma - PO - Oral administration - IV - Intravenous - CE - T1W - MRI - Contrast enhanced T1 weighted magnetic resonance imaging - CKA - Choline kinase alpha - NAB - normal- appearing brain - VOI - Volume of interest - SNR - signal-to-noise ratio - TR - Repetition time - FWHM - Full width at half maximum - FE - fractional enrichment.