A Novel Class of ¹H‐MRI Contrast Agents Based on the Relaxation Enhancement Induced on Water Protons by ¹⁴N‐Containing Imidazole Moieties

Abstract

This study reports the development of a completely new class of MRI contrast agents, displaying remarkable relaxation effects in the absence of paramagnetic metal ions. Their detection requires the acquisition of images at variable magnetic field strength as provided by fast field cycling imaging scanners. They contain poly‐histidine chains (poly‐His), whose imidazole groups generate 14N‐quadrupolar‐peaks that cause a relaxation enhancement of water protons at a frequency (1.38±0.3 MHz) that is readily detectable from the frequencies associated with endogenous proteins. The poly‐His quadrupolar peaks are detectable only when the polymer is in a solid‐like form, that is, at pH>6.6. Above this value, their intensity is pH dependent and can be used to report on the occurring pH changes. On this basis, the poly‐His moieties were conjugated to biocompatible polymers, such as polylactic and glycolic acid, in order to form stable nanoparticles able to encapsulate structured water in their core. FFC images were acquired to assess their contrast‐generating ability.

Recent advances in development of nanomedicines for multiple sclerosis diagnosis

“…They were reported to demonstrate a frequency-selective property, endowing them with the contrast tunability depending on the magnetic field frequency and the lesion site conditions [177,178]. 14 N-containing imidazole-based QRE contrast agents could also achieve frequency-selective contrast through fast field-cycling imaging [179,180]. Metal-free contrast agents are pursued to address the toxicity issue of contrast agents.…”

Monitoring tissue implants by field-cycling 1H-MRI via the detection of changes in the 14N-quadrupolar-peak from imidazole moieties incorporated in a “smart“ scaffold material

“…We have recently reported the fast and easy synthesis of PLGA-oligo-His via a thiol-Michael addition reaction between PLGA-PEG2-Maleimide and oligo-His containing a N-terminal cysteine residue (aminoacid sequence: CGGHnβA, n=15). [34] The oligo-His peptide was synthesized by standard 9-fluorenylmethyloxycarbonyl solid-phase peptide synthesis (Fmoc-SPPS) carried out on a Liberty CEM microwave synthesizer. Herein (Figure 1…”

“…However, the sensor proposed here is based on 14 N-containing compounds that are able to generate QPs clearly distinguishable from the previously known ones. We recently reported [34] that exogenous poly-Histidine (poly-His) containing systems of different sizes show a further QP in addition to the endogenous ones, thus paving the way for the development of a totally new class of metal-free 1 H-MRI frequencyencoded specific reporters. The contrast is derived from imidazole groups of oligo-histidine chains causing Quadrupolar Relaxation Enhancement (QRE) at 1.39 MHz, readily detectable by an FFC-MRI scanner.…”

Gadolinium (III)‐Chelated Deformable Mesoporous Organosilica Nanoparticles as Magnetic Resonance Imaging Contrast Agent

“…Approximately 40% of clinical MRI scans are performed with the assistance of contrast agents. [ 3 ] Gadolinium (Gd 3+ ) complexes such as Magnevist (Gd‐DTPA) are one of the most commonly used T 1 contrast agents in clinics because of their thermodynamic stable and high paramagnetic. However, the lack of tissue specificity, rapid renal clearance, and limited relaxivity of Gd‐DTPA mean higher doses during tumor imaging are required, [ 1b,4 ] which may cause potential harm to patients.…”