Manganese-based MRI contrast agent for quantitative myocardial perfusion imaging

PROJECT SUMMARY Coronary artery disease is the most common type of heart disease, and it is the leading cause of mortality in the US. Myocardial perfusion imaging (MPI) is used for non-invasive functional ischemic assessments, in the management of patients with known or suspected CAD. Qualitative MPI (most commonly with single-photon emission computed tomography or SPECT in clinical practice) is predominantly used for the evaluation of regional perfusion, but it suffers from limitations in the assessment of patients with multi-vessel disease, microvascular diffusion, and diffuse atherosclerosis. Magnetic resonance imaging (MRI) is an alternate to SPECT as it can provide a far superior spatial resolution and concomitant anatomical characterization. MRI MPI is currently done with gadolinium-based contrast agents, but this technique is also qualitative/ semi-quantitative, and Gd is contraindicated in patients with acute or chronic renal insufficiency who are also disproportionately affected by heart disease. LadeRx is developing an MRI contrast agent based on manganese chelated to bisphosphonate (MnBP), which will enable quantitative myocardial perfusion imaging with concomitant high-resolution anatomical data in a single exam. This will substantially improve the accurate diagnosis and management of patients with coronary artery disease, particularly patients with multivessel disease. In preliminary data obtained in mice, MnBP, administered intravenously at a low dose of 1mg/kg showed a stable contrast enhancement of cardiac tissue lasting >40 minutes. T he remainder of the complex was rapidly cleared from the blood via renal and liver-gallbladder pathways, avoiding unwanted deposition in other tissues. MnBP also demonstrated rapid elimination in a renally-impaired mouse model. In this Phase I STTR project, LadeRX will advance the development of the MnBP contrast agent by validating quantitative myocardial blood flow measurement and determining the pharmacokinetics profile and biodistribution of MnBP in rat. Aim 1: Demonstration of absolute myocardial blood flow (MBF) measurement with MnBP-based MRI: MR signal changes at rest and in adenosine-stressed rats will be compared to fluorescent microsphere spectroscopic determinations of absolute MBF using the same animals. Milestone: A linear relationship is obtained between MRI signal changes, relaxivity mapping and MBF. (ii) The kinetic model that enables absolute MRI MBF determinations in ml/min/vol is established. Aim 2: Determination of pharmacokinetics and biodistribution of MnBP in biological tissues at relevant and excess dosing by comparing ICP measurement of Mn and MRI T1 mapping. Milestone: Mn does not accumulate in off-target organs at optimal (1X) dosing. Accumulation is absent or limited excess (5X, 10X) dosing. An initial safety margin is determined for formal toxicology studies in higher animals in Phase II.