8 research outputs found
A manganese(II)-Based Responsive Contrast Agent Detects Glucose- Stimulated Zinc Secretion from the Mouse Pancreas and Prostate by MRI.
A Mn(II)-based zinc-sensitive MRI contrast agent, Mn(PyC3A)-BPEN, was prepared and
characterized and the agent was used in imaging experiments to detect
glucose-stimulated zinc secretion (GSZS) from the mouse pancreas and prostate in vivo. Thermodynamic and kinetic
stability tests showed that Mn(PyC3A-BPEN) has superior kinetic inertness
compared to Gd(DTPA), is less susceptible to transmetallation in the presence
of excess Zn2+
ions, and less susceptible to transchelation by albumin. In comparison with other gadolinium-based
zinc sensors bearing a single zinc binding moiety, Mn(PyC3A-BPEN) appears to be a reliable alternative for imaging b-cell function in the pancreas and
glucose-stimulated zinc secretion from prostate cells
Using micro-synchrotron radiation x-ray fluorescence (mu-SRXRF) for trace metal imaging in the development of MRI contrast agents for prostate cancer imaging
A Responsive MRI Contrast Agent for Detection of Excess copper(II) in the Liver in Vivo
The design, synthesis, and properties of a new
gadolinium-based copper-responsive MRI contrast agents are presented in detail
here. The sensor (GdL1) has high selectivity for copper ions and
exhibits a 47% increase in r1 relaxivity upon binding to 1
equivalent of Cu2+ in aqueous buffer. Interestingly, in the presence of
physiological levels of human serum albumin (HSA), the r1 relaxivity
is amplified even further up to 270%.
Additional spectroscopic and XAS studies show that Cu2+ is
coordinated by two carboxylic acid groups and the single amine group on an
appended side-chain of GdL1 and forms a ternary complex with HSA
(GdL1-Cu2+-HSA). T1-weighted in vivo imaging demonstrates that GdL1
can detect basal, endogenous labile copper(II) ions in living mice. This offers a unique opportunity to explore
the role of copper ions in the development and progression of neurological
diseases such as Wilson disease.
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Molecular magnetic resonance imaging of liver inflammation using an oxidatively activated probe
Background & Aims: Many liver diseases are driven by inflammation, but imaging to non-invasively diagnose and quantify liver inflammation has been underdeveloped. The inflammatory liver microenvironment is aberrantly oxidising owing in part to reactive oxygen species generated by myeloid leucocytes. We hypothesised that magnetic resonance imaging using the oxidatively activated probe Fe-PyC3A will provide a non-invasive biomarker of liver inflammation. Methods: A mouse model of drug-induced liver injury was generated through intraperitoneal injection of a hepatoxic dose of acetaminophen. A mouse model of steatohepatitis was generated via a choline-deficient, l-amino acid defined high-fat diet (CDAHFD). Images were acquired dynamically before and after intravenous injection of Fe-PyC3A. The contrast agent gadoterate meglumine was used as a non-oxidatively activated negative control probe in mice fed CDAHFD. The (post-pre) Fe-PyC3A injection change in liver vs. muscle contrast-to-noise ratio (ÎCNR) recorded 2 min post-injection was correlated with liver function test values, histologic scoring assigned using the NASH Clinical Research Network criteria, and intrahepatic myeloid leucocyte composition determined by flow cytometry. Results: For mice receiving i.p. injections of acetaminophen, intrahepatic neutrophil composition correlated poorly with liver test values but positively and significantly with ÎCNR (r = 0.64, p <0.0001). For mice fed CDAHFD, ÎCNR generated by Fe-PyC3A in the left lobe was significantly greater in mice meeting histologic criteria strongly associated with a diagnosis NASH compared to mice where histology was consistent with likely non-NASH (p = 0.0001), whereas no differential effect was observed using gadoterate meglumine. In mice fed CDAHFD, ÎCNR did not correlate strongly with fractional composition of any specific myeloid cell subpopulation as determined by flow cytometry. Conclusions: Magnetic resonance imaging using Fe-PyC3A merits further evaluation as a non-invasive biomarker for liver inflammation. Impact and implications: Non-invasive tests to diagnose and measure liver inflammation are underdeveloped. Inflammatory cells such as neutrophils release reactive oxygen species which creates an inflammatory liver microenvironment that can drive chemical oxidation. We recently invented a new class of magnetic resonance imaging probe that is made visible to the scanner only after chemical oxidation. Here, we demonstrate how this imaging technology could be applied as a non-invasive biomarker for liver inflammation
Amplifying the Sensitivity of Zinc(II) Responsive MRI Contrast Agents by Altering Water Exchange Rates
Given the known water exchange rate
limitations of a previously
reported ZnÂ(II)-sensitive MRI contrast agent, GdDOTA-diBPEN, new structural
targets were rationally designed to increase the rate of water exchange
to improve MRI detection sensitivity. These new sensors exhibit fine-tuned
water exchange properties and, depending on the individual structure,
demonstrate significantly improved longitudinal relaxivities (<i>r</i><sub>1</sub>). Two sensors in particular demonstrate optimized
parameters and, therefore, show exceptionally high longitudinal relaxivities
of about 50 mM<sup>â1</sup> s<sup>â1</sup> upon binding
to ZnÂ(II) and human serum albumin (HSA). This value demonstrates a
3-fold increase in <i>r</i><sub>1</sub> compared to that
displayed by the original sensor, GdDOTA-diBPEN. In addition, this
study provides important insights into the interplay between structural
modifications, water exchange rate, and kinetic stability properties
of the sensors. The new high relaxivity agents were used to successfully
image ZnÂ(II) release from the mouse pancreas <i>in vivo</i> during glucose stimulated insulin secretion