title: A Manganese Alternative to Gadolinium for MRI Contrast.
abstract: 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 KML = 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 Kd = 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.
authors.affiliation: The Athinoula A. Martinos Center for Biomedical Imaging, The Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School , 149 Thirteenth Street, Suite 2301, Charlestown, Massachusetts 02129, United States.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Gale
authors.affiliation: The Athinoula A. Martinos Center for Biomedical Imaging, The Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School , 149 Thirteenth Street, Suite 2301, Charlestown, Massachusetts 02129, United States.
authors.forename: Iliyana P
authors.initials: IP
authors.lastname: Atanasova
authors.affiliation: The Athinoula A. Martinos Center for Biomedical Imaging, The Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School , 149 Thirteenth Street, Suite 2301, Charlestown, Massachusetts 02129, United States.
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
authors.affiliation: The Athinoula A. Martinos Center for Biomedical Imaging, The Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School , 149 Thirteenth Street, Suite 2301, Charlestown, Massachusetts 02129, United States.
authors.forename: Ilknur
authors.initials: I
authors.lastname: Ay
authors.affiliation: The Athinoula A. Martinos Center for Biomedical Imaging, The Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School , 149 Thirteenth Street, Suite 2301, Charlestown, Massachusetts 02129, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Caravan
mesh_terms: D003287:Contrast Media / Q000737:chemistry*; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry; D005682:Gadolinium / Q000737:chemistry; D008279:Magnetic Resonance Imaging; D008345:Manganese / Q000737:chemistry*; D015394:Molecular Structure
chemical_list: D003287:Contrast Media; D056831:Coordination Complexes; D008345:Manganese; D005682:Gadolinium