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Novel Matrix Metalloproteinase Inhibitor [ F]Marimastat Published OnlineFirst August 20, 2010; DOI: 10.1158/0008-5472.CAN-10-1584 Therapeutics, Targets, and Chemical Biology Cancer Research Novel Matrix Metalloproteinase Inhibitor [18F]Marimastat- Aryltrifluoroborate as a Probe for In vivo Positron Emission Tomography Imaging in Cancer Ulrich auf dem Keller1, Caroline L. Bellac1, Ying Li2, Yuanmei Lou4, Philipp F. Lange1, Richard Ting2, Curtis Harwig2, Reinhild Kappelhoff1, Shoukat Dedhar4, Michael J. Adam2,6, Thomas J. Ruth2,3, François Bénard5, David M. Perrin2, and Christopher M. Overall1 Abstract Matrix metalloproteinases (MMP), strongly associated pathogenic markers of cancer, have undergone extensive drug development programs. Marimastat, a noncovalent MMP inhibitor, was conjugated with FITC to label cellular metalloproteinase cancer targets in MDA-MB-231 cells in vitro. Punctate localization of active transmembrane MMP14 was observed. For molecular-targeted positron emission tomography imaging of syn- geneic 67NR murine mammary carcinoma in vivo, marimastat was 18F-labeled using a shelf-stable arylboronic ester conjugate as a captor for aqueous [18F]fluoride in a novel, rapid one-step reaction at ambient temper- ature. [18F]Marimastat-aryltrifluoroborate localized to the tumors, with labeling being blocked in control animals first loaded with >10-fold excess unlabeled marimastat. The labeled drug cleared primarily via the hepatobiliary and gastrointestinal tract, with multiple animals imaged in independent experiments, confirming the ease of this new labeling strategy. Cancer Res; 70(19); 7562–9. ©2010 AACR. Introduction target specificity (1). Hence, cancer-specific small molecule 18F-labeled radiotracers are urgently needed. Positron emission tomography (PET) for molecular Rapid on-site production of bioactive specific molecular imaging is one of the most powerful noninvasive imaging imaging agents is hampered by 18F labeling methodologies technologies for the production of high-resolution, three- that traditionally have relied on C–F bond formation under dimensional images within deep tissue needed for human conditions that are generally incompatible with biomolecule clinical application (1). Fluorine-18 (18F) is the optimal PET stability, such as scrupulously dry organic solvents at 70°C to radioisotope because of its short half-life leading to favorable 140°C. Overcoming these obstacles is plagued by relatively radiometric dosimetry, its high sensitivity, and the ability to time-consuming multistep syntheses that are further compli- quantify tissue distribution of conjugated compounds. In- cated by side reactions requiring extensive purification. Cou- 18 18 deed, [ F]-2-deoxy-D-glucose (FDG) is the most widely used pled with the short half-life of F (110 min), these problems radiotracer for cancer diagnostics despite a relative lack of reduce specific activity and the imaging time window. Recently, Ting and colleagues (2) used arylboronate precur- sors to capture aqueous [18F]fluoride in the form of an aryl- 18 trifluoroborate (ArBF3)for F-labeling in a rapid, one-step Authors' Affiliations: 1UBC Centre for Blood Research, Departments of Oral synthesis under acidic aqueous conditions at room tempera- Biological and Medical Sciences, and Biochemistry and Molecular Biology, 18 2 3 4 ture. Indeed, the [ F]aryltrifluoroborate was stable in vivo Chemistry, and Medicine, University of British Columbia; Department of 18 Cancer Genetics and 5Molecular Oncology Department, BC Cancer Agency because no [ F]fluoride accumulation was detected in bone, Research Centre; and 6PET Chemistry Group, TRIUMF, Vancouver, British a highly fluorophilic tissue (3). Such chemistries have the Columbia, Canada potential to fast-track the introduction of 18F-labeled biocon- Note: Supplementary data for this article are available at Cancer Research jugates in “kit” form7 for diagnostic imaging in humans. Online (http://cancerres.aacrjournals.org/). To validate this novel labeling method for cancer imaging, Present address for U. auf dem Keller: Institute of Cell Biology, ETH Zurich, Schafmattstr. 18, CH-8093 Zurich, Switzerland. we hypothesized that an optimal target would be highly expressed in many tumors, show discrimination between dif- U. auf dem Keller and C.L. Bellac contributed equally to this work. ferent cancer stages, and be targeted by nanomolar inhibitor D.M. Perrin and C.M. Overall shared senior authorship. drugs with clinically demonstrated safety. These criteria are Corresponding Authors: Christopher M. Overall, University of British met by matrix metalloproteinases (MMP) that are expressed Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Phone: 604-822-2958; Fax: 604-822-7742; E-mail: [email protected] and David M. Perrin, Phone: 604-822-0567; Fax: 604-822-2847; E-mail: [email protected]. 7 Li Y, Ting R, Harwig C, et al. Kit-like 18F-labeling of small molecules with doi: 10.1158/0008-5472.CAN-10-1584 specific activities suitable for in vivo PET imaging: toward imaging cancer as- ©2010 American Association for Cancer Research. sociated matrix metalloproteases. 2010; submitted for publication. 7562 Cancer Res; 70(19) October 1, 2010 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst August 20, 2010; DOI: 10.1158/0008-5472.CAN-10-1584 In vivo PET Imaging of Proteases in Cancer and activated in most cancers and their peritumor stroma Chemical synthesis (4, 5). With many MMP inhibitor drug candidates reaching Chemicals were purchased from Sigma-Aldrich and Acros phase III clinical trials, their failure has nevertheless been Organics. Deuterated solvents were purchased from Cam- disappointing (4, 6). Marimastat, a nanomolar hydroxamate bridge Isotope Laboratories. Analytic and preparative TLC peptidic broad-spectrum MMP inhibitor (7) with activity were performed using Silica Gel 60 F254 Glass TLC plates from against related MMPs, such as the ADAMs and ADAMTSs EMD Chemicals. All 1H-nuclear magnetic resonance (NMR) that are also often associated with cancer (4, 5), is a nonco- spectra were recorded on a Bruker Avance 300 or 400 MHz valent and thereby reversible inhibitor, and thus has reduced instrument. Chemical shifts are reported using the δ scale in potential for tissue accumulation and unwanted irreversible ppm and all coupling constants (J) are reported in hertz (Hz). side reactions in short-term imaging applications. In late Unless specified, 1H-NMR spectra are referenced to the tetra- phase III clinical trials involving thousands of patients with methylsilane peak (δ = 0.00) and 19F-NMR spectra are advanced cancer, including breast carcinoma trials, marima- referenced to NEAT trifluoroacetic acid (δ = 0.00, −78.3 ppm 19 stat proved to be safe, although some patients reported relative to CFCl3). Due to the presence of F contaminations musculoskeletal pain (7). Hence, we selected marimastat as in the NMR spectrometer probe, baseline corrections for sam- a scaffold onto which a boronic acid could be grafted for ples <20 mmol/L in 19F concentration had to be adjusted by aqueous [18F]fluoride capture so as to develop a noninvasive, multipoint linear baseline correction using MestReC 4.9.9.9. clinically safe radiotracer for the in vivo imaging of cancer This correction did not affect the absolute chemical shifts or by detection of elevated MMP levels. We present the first integration ratios of 19F signals. one-step radiolabeling for in vivo application of a molecular- Final synthesis of compounds illustrated in Fig. 2A is targeted [18F]-PET probe for cancer detection and show high described below. Synthesis of precursor compounds is fully specificity labeling of mammary carcinomas in mice. detailed in Supplementary Materials and Methods (Note: if not specifically indicated, compound numbers refer to Supplementary Schemes 1 to 4). Materials and Methods Marimastat 1 Cell lines (2R,3S)-N -((S)-3,3-dimethyl-1-(methylamino)-1-oxobutan- 4 MDA-MB-231 breast carcinoma cells were kindly provided 2-yl)-N ,3-dihydroxy-2-isobutylbutanediamide (1). To a by Dr. V.C. Jordan (Northwestern University, Chicago, IL) in solution of methyl ester 5 (92 mg, 0.28 mmol) in methanol/ 2002. Stable MMP14 transfectants were established and char- THF (1:1, 0.8 mL) was added KCN (3 mg) followed by a solu- μ acterized by us as described previously (8, 9). The murine tion of hydroxylamine in H2O (50 wt%, 100 L, 1.5 mmol) and breast cancer cell line, 67NR (10), was kindly provided by the reaction stirred at room temperature for 16 hours. The Dr. Fred Miller (Karmanos Cancer Institute, Detroit, MI) in mixture was then concentrated under reduced pressure and July 2008. The cell line was authenticated for growth in vitro diluted with CH2Cl2/methanol (19:1, 2 × 10 mL). The CH2Cl2/ and in vivo as described by us previously (11). methanol washings were filtered and concentrated under reduced pressure to afford marimastat (1, 77 mg, 83%) as a 1 1 Syngeneic tumor model white solid. H-NMR (400 MHz, CD3OD) δ 4.19 (s, H), 4.01 Female BALB/c mice (7–9 weeks old; Taconic Laboratories) (d, J =6.3Hz,1H),2.82to2.79(m,1H), 2.73 (s, 3H), 1.62 to were injected with 1 × 106 viable 67NR/CMV-Luciferase mu- 1.53(m,2H),1.31to1.28(m,1H), 1.01 (s, 9H), 0.92 (d, J = rine mammary cancer cells into the right fourth mammary 6.5 Hz, 3H), 0.89 (d, J =6.5Hz,3H);13C-NMR (100 MHz, μ δ gland (50 L in PBS per mouse; ref. 11). CD3OD) 176.1, 173.5, 169.7, 73.4, 62.5, 50.0, 39.9, 35.5, 27.4, + 27.1, 26.3, 23.8, 22.6; HRMS (ESI) calculated for C15H29N3O5Na Microarray analysis (M + Na)+ 354.2005, found 354.2002 (Marimastat; Fig. 2A, 1). Primary syngeneic 67NR tumor tissues and control mam- mary glands were dissected by laser capture microdissection Marimastat-linker (11). Total cellular RNA was extracted using RNeasy (Qiagen) (15S,18R,19S)-Methyl 15-tert-butyl-19-hydroxy-18-isobutyl- and re-extracted and resuspended in 10 μL of diethylpyro- 3,14,17-trioxo-1-phenyl-2,7,10-trioxa-4,13,16-triazaicosan- carbonate-treated water.
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