New radioiodinated carboxylic and hydroxamic matrix metalloproteinase inhibitor tracers as potential tumor imaging agents

Abstract

Several studies have demonstrated a positive correlation between tumor progression and expression of extracellular proteinases such as matrix metalloproteinases (MMPs). MMP-2 and MMP-9 have become attractive targets for cancer research because of their increased expression in human malignant tumor tissues of various organs, providing a target for medical imaging techniques. Radioiodinated carboxylic and hydroxamic MMP inhibitors 2-(4'-[ (11) were synthesized by electrophilic aromatic substitution of the tributylstannyl derivatives and resulted in radiochemical yields of 60% ± 5% (n = 3) and 70% ± 5% (n = 6), respectively. In vitro zymography and enzyme assays showed high inhibition capacities of the inhibitors on gelatinases. In vivo biodistribution showed no long-term accumulation in organs and the possibility to accumulate in the tumor. These results warrant further studies of radioiodinated carboxylic and hydroxamic MMP inhibitor tracers as potential SPECT tumor imaging agents.

MMP-9 regulates both positively and negatively collagen gel contractionA nonproteolytic function of MMP-9

“…To investigate the effect of metalloproteinase inhibitors (BB-94 and TIMP-1) as well as MMP-9 antibody on rat-MMP-9 activity, in vitro activity assays were performed, as described by Oltenfreiter et al [14]. Briefly, the initial rate of cleavage of a fluorescent substrate Mca-Pro-Leu-Gly-Leu-Dpa-AlaArg-NH2 (4.5 AM) by purified rat-MMP-9 (150 nM) previously activated by using APMA ( p-aminophenylmercuric acetate, 1 mM) was measured over 20 min in the absence or presence of MMP inhibitors (BB-94, 0-10 nM; TIMP-1, ratio TIMP-1/MMP-9 of 2 and 20) or MMP-9 antibody (0-100 Ag/ ml).…”

Valine-based biphenylsulphonamide matrix metalloproteinase inhibitors as tumor imaging agents

“…1) was performed as reported previously (Oltenfreiter et al, 2004;O'Brien et al, 2000;Hanessian et al, 2001;Oltenfreiter et al, 2005b) 4'-iodo-biphenyl was purchased from Daniels Fine Chemicals Ltd. (Edmonton, Alb., Canada) and used for synthesis of the non-radioactive analogues.…”

“…The percentages of inhibition (% of inhibition) at the different inhibitor concentrations were calculated. IC50 values were obtained as previously described (O'Brien et al, 2000;Oltenfreiter et al, 2005b;Liabakk et al, 1996).…”

“…Other zinc-binding ligands that have been utilized include reverse hydroxamic acids, carboxylic acids, thiols, and thiadiazoles (Skiles et al, 2001). Tryptophane-based biphenylsulphonamide matrix metalloproteinase inhibitors were synthesized, evaluated in vitro; in vivo and as imaging agent and were published previously (Oltenfreiter et al, 2004(Oltenfreiter et al, , 2005a. Structural changes made to the biphenyl ring system, the α-position to carboxylic acid and the carboxylate moiety, have an influence on biological activity (O'Brien et al, 2000).…”

“…These compounds were synthesized via a modified method obtained from the literature (Oltenfreiter et al, 2004;O'Brien et al, 2000;Tamura et al, 1998;Hanessian et al, 2001;Oltenfreiter et al, 2005b), and evaluated in A549-inoculated mice. Metabolic studies were performed and their suitability as diagnostic agents evaluated.…”