Abstract
Dysregulated expression or activation of matrix metalloproteinases (MMPs) is observed in many kinds of live-threatening diseases. Therefore, MMP imaging for example with radiolabelled MMP inhibitors (MMPIs) potentially represents a valuable tool for clinical diagnostics using non-invasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. This work includes the organic chemical syntheses and in vitro evaluation of five iodinated barbiturate based MMPIs and the selection of derivative 9 for radiosyntheses of isotopologues [123I]9 potentially useful for MMP SPECT imaging and [124I]9 for MMP PET imaging.
Highlights
The in vivo molecular imaging of locally upregulated and activated matrix metalloproteinases (MMPs) that are observed in pathologies such as cardiovascular diseases, inflammation or cancer remains a substantive clinical issue [1]
Our own approaches towards the development of radiolabelled and fluorescent-dye conjugated MMP tracers focused on two different classes of non-peptidic MMP inhibitors (MMPIs), on the one hand hydroxamate-based inhibitors and, on the other hand, pyrimidine-2,4,6-trione-based inhibitors (i.e., barbiturates, derivatives of RO-2653 [8,9,10,11] with sub-group selectivity for the gelatinases A (MMP-2) and B (MMP-9), neutrophil collagenase (MMP-8) and the membrane-bound MMPs MT-1-MMP (MMP-14) and MT-3-MMP (MMP-16))
In 2005 we suggested in the latter project a first radiolabelled barbiturate-based MMPI, compound 12 labelled with the radionuclide iodine-125 (125I), for first in vitro and
Summary
The in vivo molecular imaging of locally upregulated and activated matrix metalloproteinases (MMPs) that are observed in pathologies such as cardiovascular diseases, inflammation or cancer remains a substantive clinical issue [1]. Current targeting strategies for noninvasive imaging of MMPs should account for high binding affinity and specificity towards the enzyme and for drug-target residence time [2], subgroup selectivity, sensitivity, target-to-background ratio as well as in vivo stability [3]. Our own approaches towards the development of radiolabelled and fluorescent-dye conjugated MMP tracers focused on two different classes of non-peptidic MMPIs, on the one hand hydroxamate-based inhibitors (i.e., derivatives of CGS 27023A and CGS 25966 [7] with a broad-spectrum inhibitory profile) and, on the other hand, pyrimidine-2,4,6-trione-based inhibitors (i.e., barbiturates, derivatives of RO-2653 [8,9,10,11] with sub-group selectivity for the gelatinases A (MMP-2) and B (MMP-9), neutrophil collagenase (MMP-8) and the membrane-bound MMPs MT-1-MMP (MMP-14) and MT-3-MMP (MMP-16)). In 2005 we suggested in the latter project a first radiolabelled barbiturate-based MMPI, compound 12 (see Table 2) labelled with the radionuclide iodine-125 (125I), for first in vitro and
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