Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 20, Issue 1, Pages 392-397Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2009.10.061
Keywords
PSMA; Glutamate carboxypeptidase II; Molecular imaging; Radiopharmaceutical; SPECT
Categories
Funding
- National Institutes of Health [MH080580, CA092871]
- U.S. Department of Energy [W-31-109-Eng38]
- National Cancer Institute, Center for Cancer Research
- NATIONAL CANCER INSTITUTE [R24CA092871, U24CA092871] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R21MH080580, R33MH080580] Funding Source: NIH RePORTER
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We report a strategy based on bioisosterism to improve the physicochemical properties of existing hydrophilic, urea-based GCPII inhibitors. Comprehensive structure-activity relationship studies of the P1' site of ZJ-43- and DCIBzL-based compounds identified several glutamate-free inhibitors with K-i values below 20 nM. Among them, compound 32d (K-i = 11 nM) exhibited selective uptake in GCPII-expressing tumors by SPECT-CT imaging in mice. A novel conformational change of amino acids in the S1' pharmacophore pocket was observed in the X-ray crystal structure of GCPII complexed with 32d. (C) 2009 Elsevier Ltd. All rights reserved.
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