Synthesis, radiosynthesis, in vitro and first in vivo evaluation of a new matrix metalloproteinase inhibitor based on γ-fluorinated α-sulfonylaminohydroxamic acid View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

Verena Hugenberg, Malte Behrends, Stefan Wagner, Sven Hermann, Michael Schäfers, Hartmuth C. Kolb, Katrin Szardenings, Joseph C. Walsh, Luis F. Gomez, Klaus Kopka, Günter Haufe

ABSTRACT

Background: To study MMP activity in vivo in disease, several radiolabeled MMP inhibitors functioning as radiotracers have been evaluated by means of SPECT and PET. Unfortunately, most of them suffer from metabolic instability, mainly hepatobiliary clearance and insufficient target binding. The introduction of a fluorine atom into MMPIs could contribute to target binding, enhance the metabolic stability and might shift the clearance towards more renal elimination. Recently developed α-sulfonylaminohydroxamic acid based γ-fluorinated inhibitors of MMP-2 and -9 provide promising fluorine interactions with the enzyme active site and high MMP inhibition potencies. The aim of this study is the (radio)synthesis of a γ-fluorinated MMP-2 and -9 inhibitor to evaluate its potential as a radiotracer to image MMP activity in vivo. Results: Two new fluorine-containing, enantiomerically pure inhibitors for MMP-2 and -9 were synthesized in a six step sequence. Both enantiomers exhibited equal inhibition potencies in the low nanomolar and subnanomolar range. LogD value indicated better water solubility compared to the CGS 25966 based analog. The most potent inhibitor was successfully radiofluorinated. In vivo biodistribution in wild type mice revealed predominantly hepatobiliary clearance. Two major radioactive metabolites were found in different organs. Defluorination of the radiotracer was not observed. Conclusion: (Radio)synthesis of a CGS based γ-fluorinated MMP inhibitor was successfully accomplished. The (S)-enantiomer, which normally shows no biological activity, also exhibited high MMP inhibition potencies, which may be attributed to additional interactions of fluorine with enzyme's active site. Despite higher hydrophilicity no significant differences in the clearance characteristics compared to non-fluorinated MMPIs was observed. Metabolically stabilizing effect of the fluorine was not monitored in vivo in wild type mice. More... »

PAGES

10

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s41181-018-0045-0

DOI

http://dx.doi.org/10.1186/s41181-018-0045-0

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1105877718

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30101186


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    "description": "Background: To study MMP activity in vivo in disease, several radiolabeled MMP inhibitors functioning as radiotracers have been evaluated by means of SPECT and PET. Unfortunately, most of them suffer from metabolic instability, mainly hepatobiliary clearance and insufficient target binding. The introduction of a fluorine atom into MMPIs could contribute to target binding, enhance the metabolic stability and might shift the clearance towards more renal elimination. Recently developed \u03b1-sulfonylaminohydroxamic acid based \u03b3-fluorinated inhibitors of MMP-2 and -9 provide promising fluorine interactions with the enzyme active site and high MMP inhibition potencies. The aim of this study is the (radio)synthesis of a \u03b3-fluorinated MMP-2 and -9 inhibitor to evaluate its potential as a radiotracer to image MMP activity in vivo.\nResults: Two new fluorine-containing, enantiomerically pure inhibitors for MMP-2 and -9 were synthesized in a six step sequence. Both enantiomers exhibited equal inhibition potencies in the low nanomolar and subnanomolar range. LogD value indicated better water solubility compared to the CGS 25966 based analog. The most potent inhibitor was successfully radiofluorinated. In vivo biodistribution in wild type mice revealed predominantly hepatobiliary clearance. Two major radioactive metabolites were found in different organs. Defluorination of the radiotracer was not observed.\nConclusion: (Radio)synthesis of a CGS based \u03b3-fluorinated MMP inhibitor was successfully accomplished. The (S)-enantiomer, which normally shows no biological activity, also exhibited high MMP inhibition potencies, which may be attributed to additional interactions of fluorine with enzyme's active site. Despite higher hydrophilicity no significant differences in the clearance characteristics compared to non-fluorinated MMPIs was observed. Metabolically stabilizing effect of the fluorine was not monitored in vivo in wild type mice.", 
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271 Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149, Münster, Germany
272 European Institute for Molecular Imaging, University of Münster, Waldeyerstr. 15, D-48149, Münster, Germany
273 Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149, Münster, Germany
274 rdf:type schema:Organization
 




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