[18F]Fluorocholine and [18F]fluoroacetate PET as imaging biomarkers to assess phosphatidylcholine and mitochondrial metabolism in preclinical models of TSC and LAM

Purpose: Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder caused by inactivating mutations of the TSC1 or TSC2 gene, characterized by multi-organ benign tumors. Lymphangioleiomyomatosis (LAM) is a diffuse proliferation of TSC2-deficient cells in the lung that occurs as a TSC manifestation or a sporadic disorder. TSC2 deficiency leads to activation of mTORC1, a master regulator of cell growth and metabolism. Biomarkers of whole-body tumor burden/metabolic activity and therapeutic response remain needed in TSC/LAM. Our preclinical studies aimed to assess feasibility of [¹⁸F]fluorocholine (FCH) and [¹⁸F]fluoroacetate (FACE) as TSC/LAM metabolic imaging biomarkers. Experimental Design: We used preclinical models of TSC and LAM to test in vivo uptake of [¹⁸F]FCH and [¹⁸F]FACE by positron emission tomography (PET). We also performed in vitro mechanistic validations of our in vivo results using nuclear magnetic resonance, mass spectrometry, Seahorse Analyzer, and stable and radioactive isotopes of acetate, fluoroacetate, and choline. Results: TSC2-deficient cells exhibit rapid uptake of [¹⁸F]FCH in vivo and can be visualized by PET imaging in preclinical models of TSC/LAM, including subcutaneous tumors and pulmonary nodules. Treatment with rapamycin (72-hr) suppressed [¹⁸F]FCH standardized uptake value (SUV) by ~50% in tumors. We found rapamycin-insensitive uptake of FACE by TSC2-deficient cells in vitro and in vivo, reflecting mitochondrial accumulation via inhibition of the TCA cycle enzyme aconitase. Conclusions: In summary, our findings provide mechanistic evidence for testing the potential of [¹⁸F]FCH and [¹⁸F]FACE as metabolic imaging biomarkers for TSC and LAM proliferative lesions, and novel insights into the metabolic reprogramming of TSC tumors.

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