Imaging of Fibroblast Activation Protein in Cancer Xenografts Using Novel (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine-Based Small Molecules
| Autor: | Xing Yang, Sridhar Nimmagadda, Ronnie C. Mease, Ala Lisok, Martin G. Pomper, Yong Du, Steven P. Rowe, Stephanie Slania, Zirui Jiang, Deepankar Das |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
congenital hereditary and neonatal diseases and abnormalities Pyrrolidines Colorectal cancer Mice SCID Article Fibroblast activation protein alpha In vivo Prostate Mice Inbred NOD Cell Line Tumor Neoplasms Drug Discovery Endopeptidases medicine Animals Humans Fluorometry neoplasms Fluorescent Dyes Serine protease biology Chemistry Melanoma Serine Endopeptidases Cancer Membrane Proteins Fibroblasts medicine.disease digestive system diseases medicine.anatomical_structure Cell culture Gelatinases biology.protein Cancer research Quinolines Molecular Medicine Heterografts |
| Zdroj: | J Med Chem |
| Popis: | Fibroblast activation protein (FAP) has become a favored target for imaging and therapy of malignancy. We have synthesized and characterized two new (4-quinolinoyl)-glycyl-2-cyanopyrrolidine-based small molecules for imaging of FAP, QCP01 and [(111)In]QCP02, using optical and single-photon computed tomography/CT, respectively. Binding of imaging agents to FAP was assessed in six human cancer cell lines of different cancer types: glioblastoma (U87), melanoma (SKMEL24), prostate (PC3), NSCLC (NCIH2228), colorectal carcinoma (HCT116), and lung squamous cell carcinoma (NCIH226). Mouse xenograft models were developed with FAP-positive U87 and FAP-negative PC3 cells to test pharmacokinetics and binding specificity in vivo. QCP01 and [(111)In]QCP02 demonstrated nanomolar inhibition of FAP at K(i) values of 1.26 and 16.20 nM, respectively. Both were selective for FAP over DPP-IV, a related serine protease. Both enabled imaging of FAP-expressing tumors specifically in vivo. [(111)In]QCP02 showed high uptake at 18.2 percent injected dose per gram in the U87 tumor at 30 min post-administration. |
| Databáze: | OpenAIRE |
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