title: Evaluation of [18F]BR420 and [18F]BR351 as radiotracers for MMP-9 imaging in colorectal cancer.
abstract: MMP-9 is a zinc-dependent endopeptidase that is involved in the proteolytic degradation of the extracellular matrix and plays an important role in cancer migration, invasion, and metastasis. The aim of this study was to evaluate the potential of MMP-tracers [18F]BR420 and [18F]BR351 for MMP-9 imaging in a colorectal cancer xenograft model. [18F]BR420 and [18F]BR351 were synthesized using an automated synthesis module. For [18F]BR420, a novel and improved radiosynthesis was developed. Plasma stability and MMP-9-targeting capacity of both radiotracers was compared in the Colo205 colorectal cancer model. MMP-9 and MMP-2 expression levels in the tumors were evaluated by immunohistochemistry and in situ zymography. μPET imaging as well as ex vivo biodistribution revealed a higher tumor uptake for [18F]BR420 (3.15% ± 0.03% ID/g vs 0.94% ± 0.18% ID/g for [18F]BR351 at 2 hours pi) but slower blood clearance compared with [18F]BR351. [18F]BR351 was quickly metabolized in plasma with 20.28% ± 5.41% of intact tracer remaining at 15 minutes postinjection (PI). By contrast, [18F]BR420 displayed a higher metabolic stability with >86% intact tracer remaining at 2 hours PI. Immunohistochemistry revealed the presence of MMP-9 and MMP-2 in the tumor tissue, which was confirmed by in situ zymography. However, an autoradiography analysis of tracer distribution in the tumors did not correlate with MMP-9 expression. [18F]BR420 displayed a higher tumor uptake and higher stability compared with [18F]BR351 but a low tumor-to-blood ratio and discrepancy between tracer distribution and MMP-9 immunohistochemistry. Therefore, both tracers will not be usefulness for MMP-9 imaging in colorectal cancer.
authors.affiliation: Department of Translational Neurosciences, University of Antwerp, Antwerp, Belgium.|Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium.|Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Naiara
authors.initials: N
authors.lastname: Vazquez
authors.affiliation: Department of Translational Neurosciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Stephan
authors.initials: S
authors.lastname: Missault
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium.|Department of Nuclear Medicine, University Hospital Antwerp, Edegem, Belgium.
authors.forename: Christel
authors.initials: C
authors.lastname: Vangestel
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Deleye
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium.|Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Thomae
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Staelens
authors.affiliation: Department of Translational Neurosciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dedeurwaerdere
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium.|Department of Nuclear Medicine, University Hospital Antwerp, Edegem, Belgium.
authors.forename: Leonie
authors.identifier: 0000-0002-5618-8191
authors.initials: L
authors.lastname: Wyffels
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging*; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D000072078:Positron Emission Tomography Computed Tomography; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics
chemical_list: C000625389:BR351 compound; C000625388:BR420 compound; D005462:Fluorine Radioisotopes; D011744:Pyrimidinones; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D020780:Matrix Metalloproteinase 9; D014633:Valine
keywords: Colo205; MMP-9; PET