MRI contrast agents can add tremendous value to a diagnostic MRI scan by aiding in the visualization of tissue and vascular abnormalities. Unfortunately, toxicity issues regarding the Gd present in commercial MRI contrast agents have been raised over the last decade. Our group is exploring new MRI contrast agents that use Mn, an essential element, as the contrast generating ion. We will present the synthesis, biophysical characterization, and distribution, metabolism, and pharmacokinetics (DMPK) properties of 10 new Mn-based MRI contrast agents. We will also compare the efficacy of our lead candidate Mn-based agents vs. commercially available Gd agents to visualize lesions in mouse models of glioma and hepatoma. The 10 new complexes derived from our previously reported Mn-PyC3A (PyC3A = N-picolyl- N,N′,N′-trans-1,2-cyclohexylenediaminetriacetate; J. Am. Chem. Soc., 2015, 137, 15548), which binds Mn with high affinity (Kd = 4 pM at pH 7.4) and is remarkably inert to Mn dissociation. We characterized the complexes by HPLC, MS, NMR, and octanol:water partition coefficient (logP) measurements, and quantified protein binding via ultrafiltration assay. Structure activity analysis indicates that (1) derivatization of the pyridine donor component of PyC3A does not strongly influence the interactions of the Mn ion with water – the key mechanism for generating effective MRI contrast, (2) relaxivity in human blood plasma is tightly correlated with increasing logP, and (3) plasma protein binding is tightly correlated with increasing logP. The imaging data indicates that our lead candidate Mn agents are equivalent to the standard of care Gd agents. We will also discuss the influence of logP and molecular structure on biodistribution and excretion path.<br/>

Structure-activity relationships for a new class of Mn-based MRI contrast agents: Magnetic relaxation, protein binding, and pharmacokinetics

255th National Meeting (2018)

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