Investigation of Hepatic Metabolism of DNP Hyperpolarized 1,4-C2 Succinate

Introduction: Succinic acid, containing two equivalent carboxylic acid carbons, is a prime molecule for use in hyperpolarization studies. Hyperpolarized succinate has many potential uses as it has been implicated as a paracrine signal for liver damage [1] and succinate dehydrogenase (SDH) has been shown to be a tumor suppressor [2]. Mutations in the SDH enzyme lead to accumulation of intracellular succinate, which inhibit hydroxylases that degrade hypoxia inducible factors (HIF) [3]. HIF is a family of transcription factors that promote angiogenesis and up-regulate glycolysis in tumor cells. A rapid and non-invasive technique of determining the activity of the SDH enzyme could potentially provide a means of investigating tumor malignancy. Hyperpolarized succinate has been shown to be successfully produced via the PHIP method [4]. With the increasing availability of DNP polarizers, we have investigated C labeled succinate polarization using the DNP method. At room temperature, succinic acid is a solid and the pure acid exhibits low solubility in water (0.74M) [5]. Whilst these disadvantages can be obviated by using the sodium salt of succinic acid, additional sodium ions could influence achievable polarization levels. We have explored the optimal succinic acid concentrations able to achieve sufficient concentration and polarization for in-vivo investigations of hepatic metabolism. Additionally, we have investigated succinate metabolism in-vivo in rats and in mouse organ homogenates.