Synthesis and preliminary biological evaluation of new radioiodinated MMP inhibitors for imaging MMP activity in vivo

Non-invasive measurement of matrix metalloproteinase (NIMP) activity it? vivo is a clinical challenge in many disease processes such as inflammation, tumor metastasis and atherosclerosis. Therefore, radioiodinated analogues of the non-peptidyl broad-spectrum MMP inhibitor (MMPI) CGS 27023A 1a were synthesized for non-invasive detection of MMP activity in vivo using single photon emission computed tomography (SPECT). The compounds Br-CGS 27023A 1b and HO-CGS 27023A Id were synthesized from the amino acid D-valine and used as precursors for radioiodinated derivatives of CGS 27023A and their non-radioactive references 1-CGS 27023A 1c and HO-I-CGS 27023A 1e. Radioiodination of the precursors with [I-123]NaI or [I-125]NaI produced the no-carrier-added MMP inhibitors [I-123] I-CGS 27023A If [I-125] I-CGS 27023A 1g, HO-[I-123] I-CGS27023A 1h, and HO-[I-125]I-CGS 27023A Ii. In vitro studies showed that the non-radioactive analogues of the MMP inhibitors exhibited affinities against gelatinase A (MMP-2) and gelatinase B (MMP-9) in the nanomolar range, comparable to the parent compound CGS 27023A. hi vivo biodistribution using HO-[I-125] I-CGS 27023A 1i in CL57 B16 mice showed rapid blood and plasma clearance and low retention in normal tissues. The preliminary biological evaluation warrant further studies of these radioiodinated NIMP inhibitors as potential new radiotracers for imaging NIMP activity in vivo. (C) 2004 Elsevier Inc. All rights reserved.