PURPOSE - 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, [(64)Cu]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 [(64)Cu]ABN-1 to detect and distinguish varying levels of PSMA in a panel of prostate tumor-bearing mouse models.
PROCEDURES - CTT-1297 was conjugated to the CB-TE1K1P chelator using click chemistry and radiolabeled with Cu-64. Internalization and binding affinity of [(64)Cu]ABN-1 was evaluated in the following cell lines having varying levels of PSMA expression: LNCaP late-passage > LNCaP early passage ≈ 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.
RESULTS - [(64)Cu]ABN-1 demonstrated excellent uptake in PSMA-positive cells in vitro, with ∼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 [(64)Cu]ABN-1 with tumor-to-muscle and tumor-to-blood ratios of 30 ± 11 and 21 ± 7, respectively, at 24 h post-injection. [(64)Cu]ABN-1 cleared through all tissues except for PSMA-positive kidneys.
CONCLUSIONS - [(64)Cu]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 [(64)Cu]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.
Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging. 2015 Nov 09 [Epub ahead of print]
Jessie R Nedrow, Joseph D Latoche, Kathryn E Day, Jalpa Modi, Tanushree Ganguly, Dexing Zeng, Brenda F Kurland, Clifford E Berkman, Carolyn J Anderson
Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA. , Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA. , Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA. , Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA. , Department of Chemistry, Washington State University, Pullman, WA, USA. , Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA. , Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA. , Department of Chemistry, Washington State University, Pullman, WA, USA. , Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA.