Tumor Contrast Enhancement and Whole-Body Elimination of the Manganese-Based Magnetic Resonance Imaging Contrast Agent Mn-PyC3A

Abstract

Objectives: The goals of this study were to compare the efficacy of the new manganese-based magnetic resonance imaging (MRI) contrast agent Mn-PyC3A to the commercial gadolinium-based agents Gd-DOTA and to Gd-EOB-DTPA to detect tumors in murine models of breast cancer and metastatic liver disease, respectively, and to quantify the fractional excretion and elimination of Mn-PyC3A in rats. Methods: T1-weighted contrast-enhanced MRI with 0.1 mmol/kg Mn-PyC3A was compared with 0.1 mmol/kg Gd-DOTA in a breast cancer mouse model (n = 8) and to 0.025 mmol/kg Gd-EOB-DTPA in a liver metastasis mouse model (n = 6). The fractional excretion, 1-day biodistribution, and 7-day biodistribution in rats after injection of 2.0 mmol/kg [ 52 Mn]Mn-PyC3A or Gd-DOTA were quantified by 52 Mn gamma counting or Gd elemental analysis. Imaging data were compared with a paired t test; biodistribution data were compared with an unpaired t test. Results: The postinjection-preinjection increases in tumor-to-muscle contrastto-noise ratio (ΔCNR) 3 minutes after injection of Mn-PyC3A and Gd-DOTA (mean ± standard deviation) were 17 ± 3.8 and 20 ± 4.4, respectively (P = 0.34). Liver-to-tumor ΔCNR values at 8 minutes postinjection of Mn-PyC3A and Gd-EOB-DTPAwere 28 ± 9.0 and 48 ± 23, respectively (P = 0.11). Mn-PyC3A is eliminated with 85% into the urine and 15% into the feces after administration to rats. The percentage of the injected doses (%ID) of Mn and Gd recovered in tissues after 1 day were 0.32 ± 0.12 and 0.57 ± 0.12, respectively (P = 0.0030), and after 7 days were 0.058 ± 0.051 and 0.19 ± 0.052, respectively (P < 0.0001). Conclusions: Mn-PyC3A provides comparable tumor contrast enhancement to Gd-DOTA in a mouse breast cancer model and is more completely eliminated than Gd-DOTA; partial hepatobiliary elimination of Mn-PyC3A enables conspicuous delayed phase visualization of liver metastases.

Unprecedented Kinetic Inertness for a Mn2+‐Bispidine Chelate: A Novel Structural Entry for Mn2+‐Based Imaging Agents

“…By analogy to other bispidine ligands, [14] we attributed the first protonation constant to one of the tertiary amine groups,while the other amine of the bispidine skeleton remains likely unprotonated in the chair-chair conformation. [14b] Further protonation steps supposedly occur on the lysine amine (logK H2 = 10.31, typical of the lysine e amine protonation constant) [15] and then on the PyC3A [3a] trans-CDTA [16] PC2A-EA [6] logK…”

L-EGCG-Mn nanoparticles as a pH-sensitive MRI contrast agent

“…Mn, an essential trace element in the human body, was shown to have a short T1 effect due to its five unpaired electrons (Reddi et al., 2009 ; Pan et al., 2011 ). Hence, Mn 2+ -based CAs have become of high interest for the development of novel MRI CAs (Gale et al., 2015 ; Erstad et al., 2019 ). In the last decade, scientists have developed numerous Mn-based NPs for tumor-specific MRI.…”

Role of gadolinium-based contrast agents in neurological disorders

“…It is cleared via both renal and hepatobiliary excretion and is eliminated from blood plasma. Furthermore, a liquid chromatography examination of blood plasma and urine reveals that Mn-PyC3A is cleared intact, without undergoing metabolism or degradation [93]. Manganese containing mangafodipir, which is no longer authorised by the European Medicines Agency for liver imaging, was recently used in a group of healthy volunteers to evaluate the dynamics of manganese enhancement of the brain.…”