title: Synthesis and preliminary biological evaluation of new radioiodinated MMP inhibitors for imaging MMP activity in vivo.
abstract: Non-invasive measurement of matrix metalloproteinase (MMP) activity in 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 1d were synthesized from the amino acid D-valine and used as precursors for radioiodinated derivatives of CGS 27023A and their non-radioactive references I-CGS 27023A 1c and HO-I-CGS 27023A 1e. Radioiodination of the precursors with [(123)I]NaI or [(125)I]NaI produced the no-carrier-added MMP inhibitors [(123)I]I-CGS 27023A 1f, [(125)I]I-CGS 27023A 1g, HO-[(123)I]I-CGS27023A 1h, and HO-[(125)I]I-CGS 27023A 1i. 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. In vivo biodistribution using HO-[(125)I]I-CGS 27023A 1i in CL57 Bl6 mice showed rapid blood and plasma clearance and low retention in normal tissues. The preliminary biological evaluation warrant further studies of these radioiodinated MMP inhibitors as potential new radiotracers for imaging MMP activity in vivo.
authors.affiliation: Department of Nuclear Medicine, University Hospital of the Westfälische Wilhelms-Universität, Muenster, Germany. kopka@uni-muenster.de
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Breyholz
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Marilyn P
authors.initials: MP
authors.lastname: Law
authors.forename: Burkhard
authors.initials: B
authors.lastname: Riemann
authors.forename: Sandra
authors.initials: S
authors.lastname: Schröer
authors.forename: Monika
authors.initials: M
authors.lastname: Trub
authors.forename: Benedicte
authors.initials: B
authors.lastname: Guilbert
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
authors.forename: Otmar
authors.initials: O
authors.lastname: Schober
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
mesh_terms: D000818:Animals; D005240:Feasibility Studies; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D010865:Pilot Projects; D011719:Pyrazines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: C097658:CGS 27023A; D006877:Hydroxamic Acids; D007457:Iodine Radioisotopes; D061965:Matrix Metalloproteinase Inhibitors; D011719:Pyrazines; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D020782:Matrix Metalloproteinases