A smart ¹⁹F and ¹H MRI probe with self‐immolative linker as a versatile tool for detection of enzymes

Abstract

Here we report on a dual-modal (19) F and (1) H MRI paramagnetic probe with a self-immolative linker, Gd-DOMF-Gal. The enzymatic conversion of this probe by β-galactosidase resulted in a simultaneous turning on of the fluorine signal and changed ability of the Gd(3+) complex to modulate the (1) H MR signal intensity of the surrounding water molecules. A versatile imaging platform for monitoring a variety of enzymes by (19) F and (1) H MRI using this molecular design is proposed.

Detecting Enzyme Activities with Exogenous MRI Contrast Agents

“…β-galactosidase can cleave a galactose moiety of a Gd(III) chelate, which causes aromatic delocalization and subsequent release of a separate 19 F-labeled ligand from a Gd(III) chelate. [42] The modular design of this agent may represent a platform technology for enzyme detection, because the galactose substrate may be easily replaced with a substrate for another enzyme.…”

New frontiers and developing applications in 19F NMR

“…Recent reports have shown evolution of both color pigment or fluorescence and 19 F NMR signal [109, 184, 185]. New β-gal (β-galactosidase) reporters simultaneously show 19 F chemical shift and 1 H contrast effects [186, 187]. …”

“…In most cases the chemical shift response is larger when the reporter moiety is aromatic, as opposed to aliphatic, and fluoronitrophenols have been popular. Proximity of the signaling fluorine to the site of cleavage is also critical, although in some cases a self-immolative cascade allows greater spacing [109, 166, 187]. …”

“…Recent reports have demonstrated a PRE approach to detecting enzyme activity or ions [109, 163–166, 187, 326]. Substrates include a 19 F moiety in close proximity to paramagnetic center exerting strong T 2 * relaxation and rendering it “invisible”.…”

“…Substrates include a 19 F moiety in close proximity to paramagnetic center exerting strong T 2 * relaxation and rendering it “invisible”. Enzyme induced molecular cleavage separates the fluorine moiety from the relaxing center producing enhanced 19 F signal and consequently revealing activity as demonstrated for caspase, β-gal [187, 326], and β-lactamase [327]. A gene reporter has been suggested using a stem-loop structured oligodeoxyribonucleotide based on a sequence for point mutated K-ras mRNA [328].…”