title: Targeting PSMA with a Cu-64 Labeled Phosphoramidate Inhibitor for PET/CT Imaging of Variant PSMA-Expressing Xenografts in Mouse Models of Prostate Cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  [(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.
  
  
  
  [(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.
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: Jessie R
authors.initials: JR
authors.lastname: Nedrow
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Latoche
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Day
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: Jalpa
authors.initials: J
authors.lastname: Modi
authors.affiliation: Department of Chemistry, Washington State University, Pullman, WA, USA.
authors.forename: Tanushree
authors.initials: T
authors.lastname: Ganguly
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: Dexing
authors.initials: D
authors.lastname: Zeng
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Kurland
authors.affiliation: Department of Chemistry, Washington State University, Pullman, WA, USA.
authors.forename: Clifford E
authors.initials: CE
authors.lastname: Berkman
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15219, USA. andersoncj@upmc.edu.|Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. andersoncj@upmc.edu.|Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. andersoncj@upmc.edu.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Anderson
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D015153:Blotting, Western; D003301:Copper Radioisotopes; D004705:Endocytosis; D008297:Male; D008819:Mice, Nude; D010756:Phosphoric Acids / Q000737:chemistry*; D000072078:Positron Emission Tomography Computed Tomography / Q000379:methods*; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D003301:Copper Radioisotopes; D010756:Phosphoric Acids; D019275:Radiopharmaceuticals; C011067:phosphoramidic acid; D017430:Prostate-Specific Antigen
keywords: Copper-64; Irreversible inhibitor; PET; PSMA; Phosphoramidate