Chronic kidney disease (CKD) afflicts 14% of the US adults and represents a foremost challenge facing public health. CKD patients suffer a higher prevalence of co-morbidities and an estimated 17% of 2010 Medicare costs were directly attributable to CKD patient healthcare. Patient management is further confounded by contraindications against the use of intravenous contrast media routinely used with computed tomography (CT) and magnetic resonance imaging (MRI) scans that physicians rely upon to diagnose irregularities in the structure and perfusion of vasculature and soft tissue. The prevalence of co-morbidities and the risk associated with contrast media both increase with decreased renal function. Thus as patients grow increasingly vulnerable physicians are forced to make key patient management decisions with limited radiologic information. Iodinated CT contrast media can cause acute and irreversible kidney injury to renally impaired patients, termed contrast-induced nephropathy (CIN). Gadolinium (Gd) used in MR contrast media is directly linked to nephrogenic systemic fibrosis (NSF) in renally impaired patients. We hypothesize that rationally designed Mn-chelates can provide an MR contrast alternative to Gd that is compatible for use in renally impaired patients. Rational molecular design can promote magnetic relaxation, limit Mn release, and promote non-renal clearance and complete whole body elimination. Furthermore, Mn is biogenic and free Mn2+ is rapidly excreted via the biliary pathway. Should a small amount of Mn release occur, dissociated ions would be incorporated within the endogenous labile Mn pool, or otherwise be excreted. We invented a rationally designed Mn-based contrast agent, termed Mn-PyC3A, that provides relaxivity equivalent to clinically used Gd contrast agents, dissociates 20x more slowly than the clinically used Magnevist, and undergoes rapid, whole body clearance via mixed renal and hepatobiliary paths. In this proposal we will prepare a small, focused library of Mn-PyC3A derivatives to optimize the efficacy and safety properties of this alternate contrast agent. We will characterize these Mn-chelates in vitro with respect to relaxivity, stability, and cell toxicity. We will then perform pilot studies in mice to evaluate in vivo efficacy, biodistribution and clearance. Stable, high relaxivity Mn-chelates will be evaluated in mouse models of cancer and compared with clinically used Gd contrast. For the Mn-chelate that shows the best combination of tumor enhancement, whole body elimination, and in vivo stability, we will evaluate acute dose toxicokinetics in normal rats and in rats with impaired renal function. The output of this work will be a validated alternative to Gd that is poised for an investigational new drug application and clinical translation.
Kidney disease patients are adversely impacted by toxicity concerns associated with contrast media routinely administered in CT and MRI examinations, which can preclude important radiologic examinations. 14% of US adults suffer from chronic kidney disease and contrast that is compatible with this patient group is sorely needed. The goal of this application is to develop new, manganese-based MRI contrast media designed for kidney disease compatibility.
|Gale, Eric M; Wey, Hsiao-Ying; Ramsay, Ian et al. (2018) A Manganese-based Alternative to Gadolinium: Contrast-enhanced MR Angiography, Excretion, Pharmacokinetics, and Metabolism. Radiology 286:865-872|
|Gale, Eric M; Caravan, Peter (2018) Gadolinium-Free Contrast Agents for Magnetic Resonance Imaging of the Central Nervous System. ACS Chem Neurosci 9:395-397|
|Gale, Eric M; Caravan, Peter; Rao, Anil G et al. (2017) Gadolinium-based contrast agents in pediatric magnetic resonance imaging. Pediatr Radiol 47:507-521|
|Gale, Eric M; Jones, Chloe M; Ramsay, Ian et al. (2016) A Janus Chelator Enables Biochemically Responsive MRI Contrast with Exceptional Dynamic Range. J Am Chem Soc 138:15861-15864|