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Accelerated 19F·MRI Detection of Matrix Metalloproteinase-2/-9 through Responsive Deactivation of Paramagnetic Relaxation Enhancement

Faas, Henryk M.; Krupa, James L.; Taylor, Alexander J.; Zamberlan, Francesco; Philp, Christopher J.; Williams, Huw E.L.; Johnson, Simon R.; Pavlovskaya, Galina E.; Thomas, Neil R.; Meersmann, Thomas

Accelerated 19F·MRI Detection of Matrix Metalloproteinase-2/-9 through Responsive Deactivation of Paramagnetic Relaxation Enhancement Thumbnail


Authors

Henryk M. Faas

James L. Krupa

Alexander J. Taylor

Francesco Zamberlan

Christopher J. Philp

HUW WILLIAMS HUW.WILLIAMS@NOTTINGHAM.AC.UK
Senior Research Fellow

SIMON JOHNSON simon.johnson@nottingham.ac.uk
Professor of Respiratory Medicine

NEIL THOMAS neil.thomas@nottingham.ac.uk
Professor of Medicinal and Biological Chemistry

THOMAS MEERSMANN thomas.meersmann@nottingham.ac.uk
Professor of Translational Imaging



Abstract

Paramagnetic gadolinium ions (Gd III), complexed within DOTA-based chelates, have become useful tools to increase the magnetic resonance imaging (MRI) contrast in tissues of interest. Recently, " on/off " probes serving as 19 F·MRI biosensor for target enzymes have emerged that utilize the increase in transverse (T * 2 or T 2) relaxation times upon cleavage of the paramagnetic Gd III centre. Molecular 19 F·MRI has the advantage of high specificity due to the lack of background signal but suffers from low signal intensity that leads to low spatial resolution and long recording times. In this work, an " on/off " probe concept is introduced that utilizes responsive deactivation of paramagnetic relaxation enhancement (PRE) to generate 19 F longitudinal (T 1) relaxation contrast for accelerated molecular MRI. Matrix metalloproteinases (MMPs), a class of enzymes linked with many inflammatory diseases and cancer, modify bioactive extracellular substrates and present therefore an accessible target for responsive PRE deactivation probes. Responsive PRE deactivation in a 19 F biosensor probe, selective for MMP-2 and MMP-9, is shown to enable molecular MRI contrast at significantly reduced experimental times compared to previous methods. PRE deactivation was caused by MMP through cleavage of a protease substrate that served as a linker between the fluorine-containing moiety and a para-magnetic Gd III-bound DOTA complex. Ultrashort echo time (UTE) MRI and, alternatively, short echo times in standard gradient echo (GE) MRI were employed to cope with the fast 19 F transverse relaxation of the PRE active probe in its " on-state. " Upon responsive PRE deactivation, the 19 F·MRI signal from the " off-state " probe diminished, thereby indicating the presence of the target enzyme through the associated negative MRI contrast. Null point 1 H·MRI, obtainable within a short time course, was employed to identify false-positive 19 F·MRI responses caused by dilution of the contrast agent.

Journal Article Type Article
Acceptance Date Dec 8, 2018
Online Publication Date Feb 28, 2019
Publication Date Feb 28, 2019
Deposit Date Apr 9, 2019
Publicly Available Date Apr 9, 2019
Journal Contrast Media and Molecular Imaging
Print ISSN 1555-4309
Electronic ISSN 1555-4317
Publisher Hindawi
Peer Reviewed Peer Reviewed
Volume 2019
Article Number 4826520
Pages 1-13
DOI https://doi.org/10.1155/2019/4826520
Keywords Radiology Nuclear Medicine and imaging
Public URL https://nottingham-repository.worktribe.com/output/1590231
Publisher URL https://www.hindawi.com/journals/cmmi/2019/4826520/