Membrane Type 1 Matrix Metalloproteinase Detection in Tumors, Using the Iodinated Endogenous [123I]-Tissue Inhibitor 2 of Metalloproteinases as Imaging Agent

Abstract

Matrix metalloproteinases (MMPs) are principal participants in tumor development. In addition to serve as a useful biochemical marker, MMP expression may also provide a target for the diagnostic in vivo imaging of tumors, using a radiolabeled inhibitor. This study investigates the use of membrane type 1 (MT1)-MMP as target for in vivo tumor diagnosis. Specific binding of the endogenous tissue inhibitor of metalloproteinase-2 (TIMP-2) to MT1-MMP has been previously described. In this study, biodistribution and imaging experiments were performed on MT1-MMP-overexpressing (S.1.5) and control (C.IV.3) tumor-inoculated mice using [(123)I]-recombinant human TIMP-2 (rhTIMP-2) as radioligand and [(123)I]-rhTIMP-1 as control. The expression profile was controlled in vitro and on tumor extracts. rhTIMP-2 as well as rhTIMP-1 were labeled using the Iodogen method and characterized. Biodistribution of [(123)I]-rhTIMP-2 showed a tumor uptake of 2.87% ± 1.58% ID/g at 3 hours postinjection in S.1.5. Tumor values of [(123)I]-rhTIMP-1 and [(123)I]-rhTIMP-2 evaluated in S.1.5 and C.IV.3, respectively, were significantly lower. Planar imaging revealed significant uptake of [(123)I]-rhTIMP-2 in S.1.5 compared with contralateral background areas. This could not be observed in C.IV.3 and with [(123)I]-rhTIMP-1 in S.1.5. All tumors were well established (200-800 mg). These results suggest that rhTIMP-2 holds potential for development of radiotracers for in vivo imaging in overexpressing MT1-MMP but not in similar tumors that do not express this protease.