A Manganese Alternative to Gadolinium for MRI Contrast

• Published in: Journal of the American Chemical Society Vol. 137; no. 49; pp. 15548 - 15557
• Main Authors: Gale, Eric M, Atanasova, Iliyana P, Blasi, Francesco, Ay, Ilknur, Caravan, Peter
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.12.2015; Amer Chemical Soc
• Subjects: animal models; blood plasma; chelates; chelating agents; Chemistry; Chemistry, Multidisciplinary; computed tomography; Contrast Media - chemistry; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; dissociation; fibrin; gadolinium; Gadolinium - chemistry; image analysis; kidney diseases; Magnetic Resonance Imaging; manganese; Manganese - chemistry; metabolites; Molecular Structure; patients; Physical Sciences; Science & Technology; thrombosis; United States; zinc; United States; ANGIOGRAPHY; DENTATE NUCLEUS; EP-2104R; AGENTS; RELAXIVITY; HIGH SIGNAL INTENSITY; MN2+ COMPLEXES; METAL-COMPLEXES; NEPHROGENIC SYSTEMIC FIBROSIS; FIBRIN
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.5b10748

Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used to diagnose soft tissue and vascular abnormalities. However, safety concerns limit the use of iodinated and gadolinium (Gd)-based CT and MRI contrast media in renally compromised patients. With an estimated 14% of the US population suffering from chronic kidney disease (CKD), contrast media compatible with renal impairment is sorely needed. We present the new manganese­(II) complex [Mn­(PyC3A)­(H2O)]− as a Gd alternative. [Mn­(PyC3A)­(H2O)]− is among the most stable Mn­(II) complexes at pH 7.4 (log K ML = 11.40). In the presence of 25 mol equiv of Zn at pH 6.0, 37 °C, [Mn­(PyC3A)­(H2O)]− is 20-fold more resistant to dissociation than [Gd­(DTPA)­(H2O)]2–. Relaxivity of [Mn­(PyC3A)­(H2O)]− in blood plasma is comparable to commercial Gd contrast agents. Biodistribution analysis confirms that [Mn­(PyC3A)­(H2O)]− clears via a mixed renal/hepatobiliary pathway with >99% elimination by 24 h. [Mn­(PyC3A)­(H2O)]− was modified to form a bifunctional chelator and 4 chelates were conjugated to a fibrin-specific peptide to give Mn-FBP. Mn-FBP binds the soluble fibrin fragment DD­(E) with K d = 110 nM. Per Mn relaxivity of Mn-FBP is 4-fold greater than [Mn­(PyC3A)­(H2O)]− and increases 60% in the presence of fibrin, consistent with binding. Mn-FBP provided equivalent thrombus enhancement to the state of the art Gd analogue, EP-2104R, in a rat model of arterial thrombosis. Mn metabolite analysis reveals no evidence of dechelation and the probe was >99% eliminated after 24 h. [Mn­(PyC3A)­(H2O)]− is a lead development candidate for an imaging probe that is compatible with renally compromised patients.