A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging

Development of matrix metalloproteinase-targeted probes for lung inflammation detection with positron emission tomography

“…The IC 50 values of ML5, I-ML5, PFB, IPFB, PFP and IPFP toward the various MMPs are summarized in Table 1 . ML5 exhibited high affinity for MMP-12 and moderate affinities for MMP-2, MMP-9 and MMP-13, consistent with a previous report 14 . The iodinated compounds (I-ML5, IPFB, and IPFP) exhibited higher affinities toward all MMPs tested than the corresponding deiodinated compounds (ML5, PFB, and PFP).…”

“…We developed an 18 F-labeled PET imaging probe for imaging MMP-12 and MMP-9 based on the inhibitor ML5 using 18 F-NFP as a prosthetic agent, in contrast to a previous report using 18 F-SFB 14 . Compared with 18 F-SFB, 18 F-NFP provides a smaller radioactive moiety, without an aromatic ring, to the inhibitor, so that the labeling procedure has fewer effects on the resulting properties of the inhibitor, such as affinity, specificity, and pharmacokinetics.…”

“…Recently, a peptidomimetic inhibitor, namely ML5, originally synthesized by Leeuwenburgh et al . 12 , 13 , which consists of a succinylhydroxamate attached to the N -terminus of phenylalanine-lysine dipeptide, was reported to show high and moderate binding affinities to MMP-12 and MMP-9, respectively, in a fluorogenic inhibition assay (IC 50 = 2.0 nM and 19.5 nM for MMP-12 and MMP-9, respectively 14 ). Moreover, ML5 is a useful lead compound due to availability of the ε-amino group of the lysine residue for radiolabeling to develop in vivo molecular imaging probes.…”

“…Moreover, ML5 is a useful lead compound due to availability of the ε-amino group of the lysine residue for radiolabeling to develop in vivo molecular imaging probes. However, ML5 radiolabeled with N -succinimidyl 4- 18 F-fluorobenzoate ( 18 F-SFB), 18 F-FB-ML5, exhibited an ~100-fold loss of affinity for MMP-12 compared to the parent compound (IC 50 = 138.0 nM and 31.5 nM for MMP-12 and MMP-9, respectively 14 ), which led to fairly diminished performance in in vivo experiments using tumor bearing mice 14 and short-term CS exposed mice 15 .…”

X-ray Structures of Succinimidyl Halobenzoates

“…Various ways to prepare the halogenated succinimidyl esters are known from the literature. Several are based on the Steglich esterification of N-hydroxy succinimide with the halobenzoic acid and DCC, EDC or TSTU as coupling reagent [11,[29][30][31][32][33]. Others used halobenzyl alcohols under radical conditions [34,35] or halobenzoic acid and N,N′-succinimidyl carbonate [36].…”