Each year millions of individuals suffer from myocardial infarction (MI) or heart attack. Diagnosis of MI is dependent on a complex set of tests which include imaging, cardiac troponin levels in plasma, and electrocardiogram. Viability assessment and myocardial perfusion imaging by radiolabeled tracers has the most impact on the diagnosis and risk assessment of MI. However, perfusion scans are unable to discriminate between an ischemic region and a necrotic region because both show reduced perfusion. They also fail to differentiate an acute infarct from an event that occurred in the past. To enable sensitive and specific imaging of acute MI, Hexakit, Inc. is collaborating with University of Oklahoma health Sciences Center (OUHSC) in development of fluorine-18-labeled fluorodeoxyglucaric acid (FGA) as the first agent meant for positron emission tomography (PET) of acute MI. PET is a superior imaging technology because of its high resolution, sensitivity, and lack of attenuation. OUHSC researchers have developed a novel technique of synthesizing FGA from commercially available F-18-labeled fluorodeoxyglucose (FDG). The reaction is quantitative and quick, as 100% of FDG is oxidatively converted into FGA within 3 min of reaction that produces no side products. Preliminary PET imaging in a model of isoproterenol-induced cardiomyopathy demonstrated significant uptake of FGA in infarcted myocardium as compared to the normal heart. At the same time, FGA undergoes rapid clearance from the body and does not accumulate in normal myocardium or surrounding normal organs which would otherwise create artifacts and/or high background in the images.
The specific aim of this proposed Phase I research from Hexakit, Inc. is to test a kit for FGA synthesis for detection of focal MI in a mouse coronary artery ligation model. This model is the most acceptable representation of human MI for testing myocardial diagnostic and therapeutic agents. We have developed a working kit of lyophilized reagents (Fig. 1b). To accomplish the following tasks we have a team with radio-chemistry/-pharmacy, PET nuclear cardiology, and interventional cardiology expertise. Task 1: Determine optimal time of FGA/PET imaging (with respect to FGA injection) Task 2: Determine how long FGA/PET remains positive post-MI and compare it to Tc-99m-MIBI perfusion imaging Task 3: Correlate FGA/PET findings with plasma troponin levels and histology of heart Task 4: Determine the mechanistic target of FGA in cardiac cells and tissue Successful accomplishment of the above tasks will position Hexakit, Inc. to assess data and prepare for a pre-IND meeting with FDA for rapid clinical translation of FGA/PET in the 2nd Phase of this STTR. A specific niche for FGA/PET will be in therapeutic decision making, determination of candidacy for revascularization, and acute assessment of revascularization success with high sensitivity and specificity. In addition, FGA/PET will complement existing diagnostic modalities to differentiate ischemia from necrosis in acute MI, discriminate myocarditis from infarction, and surveillance of heart transplant rejection.
Hexakit Inc. proposes to develop glucaric acid labeled with radionuclide fluorine-18 as a new imaging agent for positron emission tomography (PET) of acute myocardial infarction (MI). This agent will be tested in a mouse model. By enabling early detection of MI, F-18-labeled glucaric acid is predicted to improve outcomes of medical therapy or surgical intervention in these patients.