4.4 Article

Targeting PSMA with a Cu-64 Labeled Phosphoramidate Inhibitor for PET/CT Imaging of Variant PSMA-Expressing Xenografts in Mouse Models of Prostate Cancer

期刊

MOLECULAR IMAGING AND BIOLOGY
卷 18, 期 3, 页码 402-410

出版社

SPRINGER
DOI: 10.1007/s11307-015-0908-7

关键词

PSMA; PET; Copper-64; Phosphoramidate; Irreversible inhibitor

资金

  1. NIH/NCI [R01CA140617]
  2. Department of Energy/NIBIB [DE-SC0008833]
  3. NCI [P30CA047904]
  4. U.S. Department of Energy (DOE) [DE-SC0008833] Funding Source: U.S. Department of Energy (DOE)

向作者/读者索取更多资源

Prostate-specific membrane antigen (PSMA) is highly up-regulated in prostate tumor cells, providing an ideal target for imaging applications of prostate cancer. CTT-1297 (IC50 = 27 nM) is an irreversible phosphoramidate inhibitor of PSMA that has been conjugated to the CB-TE1K1P chelator for incorporation of Cu-64. The resulting positron emission tomography (PET) agent, [Cu-64]ABN-1, was evaluated for selective uptake both in vitro and in vivo in PSMA-positive cells of varying expression levels. The focus of this study was to assess the ability of [Cu-64]ABN-1 to detect and distinguish varying levels of PSMA in a panel of prostate tumor-bearing mouse models. CTT-1297 was conjugated to the CB-TE1K1P chelator using click chemistry and radiolabeled with Cu-64. Internalization and binding affinity of [Cu-64]ABN-1 was evaluated in the following cell lines having varying levels of PSMA expression: LNCaP late-passage > LNCaP early passage a parts per thousand C4-2B > CWR22rv1 and PSMA-negative PC-3 cells. PET/X-ray computed tomography imaging was performed in NCr nude mice with subcutaneous tumors of the variant PSMA-expressing cell lines. [Cu-64]ABN-1 demonstrated excellent uptake in PSMA-positive cells in vitro, with similar to 80 % internalization at 4 h for each PSMA-positive cell line with uptake (fmol/mg) correlating to PSMA expression levels. The imaging data indicated significant tumor uptake in all models. The biodistribution for late-passage LNCaP (highest PSMA expression) demonstrated the highest specific uptake of [Cu-64]ABN-1 with tumor-to-muscle and tumor-to-blood ratios of 30 +/- 11 and 21 +/- 7, respectively, at 24 h post-injection. [Cu-64]ABN-1 cleared through all tissues except for PSMA-positive kidneys. [Cu-64]ABN-1 demonstrated selective uptake in PSMA-positive cells and tumors, which correlated to the level of PSMA expression. The data reported herein suggest that [Cu-64]ABN-1 will selectively target and image variant PSMA expression and in the future will serve as a non-invasive method to follow the progression of prostate cancer in men.

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