Synthesis and preliminary evaluation in tumor bearing mice of new 18F-labeled arylsulfone matrix metalloproteinase inhibitors as tracers for positron emission tomography

Francesca Casalini, Lorenza Fugazza, Giovanna Esposito, Claudia Cabella, Chiara Brioschi, Alessia Cordaro, Luca D'Angeli, Antonietta Bartoli, Azzurra M. Filannino, Concetta V. Gringeri, Dario L. Longo, Valeria Muzio, Elisa Nuti, Elisabetta Orlandini, Gianluca Figlia, Angelo Quattrini, Lorenzo Tei, Giuseppe Digilio, Armando Rossello, Alessandro Maiocchi

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

New fluorinated, arylsulfone-based matrix metalloproteinase (MMP) inhibitors containing carboxylate as the zinc binding group were synthesized as radiotracers for positron emission tomography. Inhibitors were characterized by Ki for MMP-2 in the nanomolar range and by a fair selectivity for MMP-2/9/12/13 over MMP-1/3/14. Two of these compounds were obtained in the 18F-radiolabeled form, with radiochemical purity and yield suitable for preliminary studies in mice xenografted with a human U-87 MG glioblastoma. Target density in xenografts was assessed by Western blot, yielding B max/Kd = 14. The biodistribution of the tracer was dominated by liver uptake and hepatobiliary clearance. Tumor uptake of 18F-labeled MMP inhibitors was about 30% that of [ 18F]fluorodeoxyglucose. Accumulation of radioactivity within the tumor periphery colocalized with MMP-2 activity (evaluated by in situ zimography). However, specific tumor uptake accounted for only 18% of total uptake. The aspecific uptake was ascribed to the high binding affinity between the radiotracer and serum albumin.

Original languageEnglish
Pages (from-to)2676-2689
Number of pages14
JournalJournal of Medicinal Chemistry
Volume56
Issue number6
DOIs
Publication statusPublished - Mar 28 2013

Fingerprint

Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinase 2
Positron-Emission Tomography
Matrix Metalloproteinase 3
Neoplasms
Matrix Metalloproteinase 1
Matrix Metalloproteinase 9
Fluorodeoxyglucose F18
Glioblastoma
Heterografts
Serum Albumin
Radioactivity
Zinc
Western Blotting
Liver

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and preliminary evaluation in tumor bearing mice of new 18F-labeled arylsulfone matrix metalloproteinase inhibitors as tracers for positron emission tomography. / Casalini, Francesca; Fugazza, Lorenza; Esposito, Giovanna; Cabella, Claudia; Brioschi, Chiara; Cordaro, Alessia; D'Angeli, Luca; Bartoli, Antonietta; Filannino, Azzurra M.; Gringeri, Concetta V.; Longo, Dario L.; Muzio, Valeria; Nuti, Elisa; Orlandini, Elisabetta; Figlia, Gianluca; Quattrini, Angelo; Tei, Lorenzo; Digilio, Giuseppe; Rossello, Armando; Maiocchi, Alessandro.

In: Journal of Medicinal Chemistry, Vol. 56, No. 6, 28.03.2013, p. 2676-2689.

Research output: Contribution to journalArticle

Casalini, F, Fugazza, L, Esposito, G, Cabella, C, Brioschi, C, Cordaro, A, D'Angeli, L, Bartoli, A, Filannino, AM, Gringeri, CV, Longo, DL, Muzio, V, Nuti, E, Orlandini, E, Figlia, G, Quattrini, A, Tei, L, Digilio, G, Rossello, A & Maiocchi, A 2013, 'Synthesis and preliminary evaluation in tumor bearing mice of new 18F-labeled arylsulfone matrix metalloproteinase inhibitors as tracers for positron emission tomography', Journal of Medicinal Chemistry, vol. 56, no. 6, pp. 2676-2689. https://doi.org/10.1021/jm4001743
Casalini, Francesca ; Fugazza, Lorenza ; Esposito, Giovanna ; Cabella, Claudia ; Brioschi, Chiara ; Cordaro, Alessia ; D'Angeli, Luca ; Bartoli, Antonietta ; Filannino, Azzurra M. ; Gringeri, Concetta V. ; Longo, Dario L. ; Muzio, Valeria ; Nuti, Elisa ; Orlandini, Elisabetta ; Figlia, Gianluca ; Quattrini, Angelo ; Tei, Lorenzo ; Digilio, Giuseppe ; Rossello, Armando ; Maiocchi, Alessandro. / Synthesis and preliminary evaluation in tumor bearing mice of new 18F-labeled arylsulfone matrix metalloproteinase inhibitors as tracers for positron emission tomography. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 6. pp. 2676-2689.
@article{8b4cf90d92ab43018b41b058d65711b9,
title = "Synthesis and preliminary evaluation in tumor bearing mice of new 18F-labeled arylsulfone matrix metalloproteinase inhibitors as tracers for positron emission tomography",
abstract = "New fluorinated, arylsulfone-based matrix metalloproteinase (MMP) inhibitors containing carboxylate as the zinc binding group were synthesized as radiotracers for positron emission tomography. Inhibitors were characterized by Ki for MMP-2 in the nanomolar range and by a fair selectivity for MMP-2/9/12/13 over MMP-1/3/14. Two of these compounds were obtained in the 18F-radiolabeled form, with radiochemical purity and yield suitable for preliminary studies in mice xenografted with a human U-87 MG glioblastoma. Target density in xenografts was assessed by Western blot, yielding B max/Kd = 14. The biodistribution of the tracer was dominated by liver uptake and hepatobiliary clearance. Tumor uptake of 18F-labeled MMP inhibitors was about 30{\%} that of [ 18F]fluorodeoxyglucose. Accumulation of radioactivity within the tumor periphery colocalized with MMP-2 activity (evaluated by in situ zimography). However, specific tumor uptake accounted for only 18{\%} of total uptake. The aspecific uptake was ascribed to the high binding affinity between the radiotracer and serum albumin.",
author = "Francesca Casalini and Lorenza Fugazza and Giovanna Esposito and Claudia Cabella and Chiara Brioschi and Alessia Cordaro and Luca D'Angeli and Antonietta Bartoli and Filannino, {Azzurra M.} and Gringeri, {Concetta V.} and Longo, {Dario L.} and Valeria Muzio and Elisa Nuti and Elisabetta Orlandini and Gianluca Figlia and Angelo Quattrini and Lorenzo Tei and Giuseppe Digilio and Armando Rossello and Alessandro Maiocchi",
year = "2013",
month = "3",
day = "28",
doi = "10.1021/jm4001743",
language = "English",
volume = "56",
pages = "2676--2689",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "6",

}

TY - JOUR

T1 - Synthesis and preliminary evaluation in tumor bearing mice of new 18F-labeled arylsulfone matrix metalloproteinase inhibitors as tracers for positron emission tomography

AU - Casalini, Francesca

AU - Fugazza, Lorenza

AU - Esposito, Giovanna

AU - Cabella, Claudia

AU - Brioschi, Chiara

AU - Cordaro, Alessia

AU - D'Angeli, Luca

AU - Bartoli, Antonietta

AU - Filannino, Azzurra M.

AU - Gringeri, Concetta V.

AU - Longo, Dario L.

AU - Muzio, Valeria

AU - Nuti, Elisa

AU - Orlandini, Elisabetta

AU - Figlia, Gianluca

AU - Quattrini, Angelo

AU - Tei, Lorenzo

AU - Digilio, Giuseppe

AU - Rossello, Armando

AU - Maiocchi, Alessandro

PY - 2013/3/28

Y1 - 2013/3/28

N2 - New fluorinated, arylsulfone-based matrix metalloproteinase (MMP) inhibitors containing carboxylate as the zinc binding group were synthesized as radiotracers for positron emission tomography. Inhibitors were characterized by Ki for MMP-2 in the nanomolar range and by a fair selectivity for MMP-2/9/12/13 over MMP-1/3/14. Two of these compounds were obtained in the 18F-radiolabeled form, with radiochemical purity and yield suitable for preliminary studies in mice xenografted with a human U-87 MG glioblastoma. Target density in xenografts was assessed by Western blot, yielding B max/Kd = 14. The biodistribution of the tracer was dominated by liver uptake and hepatobiliary clearance. Tumor uptake of 18F-labeled MMP inhibitors was about 30% that of [ 18F]fluorodeoxyglucose. Accumulation of radioactivity within the tumor periphery colocalized with MMP-2 activity (evaluated by in situ zimography). However, specific tumor uptake accounted for only 18% of total uptake. The aspecific uptake was ascribed to the high binding affinity between the radiotracer and serum albumin.

AB - New fluorinated, arylsulfone-based matrix metalloproteinase (MMP) inhibitors containing carboxylate as the zinc binding group were synthesized as radiotracers for positron emission tomography. Inhibitors were characterized by Ki for MMP-2 in the nanomolar range and by a fair selectivity for MMP-2/9/12/13 over MMP-1/3/14. Two of these compounds were obtained in the 18F-radiolabeled form, with radiochemical purity and yield suitable for preliminary studies in mice xenografted with a human U-87 MG glioblastoma. Target density in xenografts was assessed by Western blot, yielding B max/Kd = 14. The biodistribution of the tracer was dominated by liver uptake and hepatobiliary clearance. Tumor uptake of 18F-labeled MMP inhibitors was about 30% that of [ 18F]fluorodeoxyglucose. Accumulation of radioactivity within the tumor periphery colocalized with MMP-2 activity (evaluated by in situ zimography). However, specific tumor uptake accounted for only 18% of total uptake. The aspecific uptake was ascribed to the high binding affinity between the radiotracer and serum albumin.

UR - http://www.scopus.com/inward/record.url?scp=84875716321&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875716321&partnerID=8YFLogxK

U2 - 10.1021/jm4001743

DO - 10.1021/jm4001743

M3 - Article

C2 - 23458498

AN - SCOPUS:84875716321

VL - 56

SP - 2676

EP - 2689

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 6

ER -