This proposal focuses on the development and validation of glutamine-derived 11C isotopomers for positron emission tomography. Specifically, the 1- and 5-positions of exogenously administered glutamine have different metabolic fates, depending on the dominant mechanisms of conversion present. We will therefore synthesize both L-[1-11C]glutamine ([1-11C]gln) and L-[5-11C]glutamine ([5-11C]gln), and investigate their use in detecting the isocitrate dehydrogenase mutation (IDHm), seen in several benign and malignant clinical diseases including low-grade glioma (LGG). Improved diagnosis of LGG would address a major challenge that neuro-radiologists, neuro-oncologists, radiation oncologists and neuro-surgeons encounter frequently, namely differentiating glial tumor from other brain entities. Patients with IDH-mutant (IDHm) glioma harbor the oncometabolite 2-hydroxyglutarate (2HG), which represents a promising way to detect LGG. We are motivated by a recent report establishing rapid conversion of exogenous glutamine to 2HG in IDHm lesions, representing a way to sequester the 11C radionuclide. The central hypothesis of this proposal is that a positron- labelled metabolic precursor of 2HG, [1-11C]gln, can be used to detect IDHm. We further predict significant advantages in using [1-11C]gln versus the reported [5-11C]gln isotopomer, based on the suppression of background signals related to tricarboxylic acid (TCA) cycle metabolism. When validated, this approach would set the stage for clinical use of [1-11C]gln PET in evaluating LGG and other IDHm lesions. We propose a multi-PI and interdisciplinary collaboration to validate [1-11C]gln PET as an IDHm-specific tool and perform the first patient studies using [1-11C]gln to further support the methodology. We will first develop the first radiosynthesis of [1-11C]gln, via adaptation of reported methods using [11C]CO2 and [11C]CN-. We will then compare the accumulation of [1-11C]gln to that of [5-11C]gln in IDHm versus IDH-wildtype (IDHwt) cells, both in vitro and in vivo (Specific Aim 1). In Specific Aim 2, all regulatory work and site approvals needed to study [1-11C]gln at UCSF will be accomplished. In Specific Aim 3, we will translate [1-11C]gln under the Radioactive Drug Research Committee (RDRC) program and study its performance in patients suffering from LGG. While this application focuses on LGG, a clinically translatable IDHm-specific tracer would revolutionize the workup and management of a large variety of clinically relevant lesions. Furthermore, robust methods to synthesize and evaluate amino-acid derived 11C isotopomers will dramatically improve the ability of PET to detect metabolic reprogramming in human disease.

PROJECT NARRATIVE: This grant application describes a way differentially label the amino acid glutamine for positron emission tomography (“PET scan”). The technology can be used to follow the metabolic fates of different positions in the molecule, potentially detecting specific enzyme mutations. The proposed technique is both simple and safe with the goal of rapid use in patients.