title: 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen: pharmacokinetics and biodistribution studies in healthy subjects and patients with metastatic prostate cancer.
abstract: Prostate-specific membrane antigen (PSMA) is a well-established target for developing radiopharmaceuticals for imaging and therapy of prostate cancer (PCa). We have recently reported that novel (99m)Tc-labeled small-molecule PSMA inhibitors bind with high affinity to PSMA-positive tumor cells in vitro and localize in PCa xenografts. This study reports the first, to our knowledge, human data in men with metastatic PCa and in healthy male subjects.
  
  
  METHODS
  Under an exploratory investigational new drug, using a cross-over design, we compared the pharmacokinetics, biodistribution, and tumor uptake of (99m)Tc-MIP-1404 and (99m)Tc-MIP-1405 in 6 healthy men and 6 men with radiographic evidence of metastatic PCa. Whole-body images were obtained at 10 min and 1, 2, 4, and 24 h. SPECT was performed between 3 and 4 h after injection.
  
  
  RESULTS
  Both agents cleared the blood rapidly, with MIP-1404 demonstrating significantly lower urinary activity (7%) than MIP-1405 (26%). Both agents showed persistent uptake in the salivary, lacrimal, and parotid glands. Uptake in the liver and kidney was acceptable for imaging at 1-2 h. In men with PCa, both agents rapidly localized in bone and lymph node lesions as early as 1 h. SPECT demonstrated excellent lesion contrast. Good correlation was seen with bone scanning; however, more lesions were demonstrated with (99m)Tc-MIP-1404 and (99m)Tc-MIP-1405. The high-contrast images exhibited tumor-to-background ratios from 3:1 to 9:1 at 4 and 20 h.
  
  
  CONCLUSIONS
  Compared with the standard-of-care bone scanning, (99m)Tc-MIP-1404 and (99m)Tc-MIP-1405 identified most bone metastatic lesions and rapidly detected soft-tissue PCa lesions including subcentimeter lymph nodes. Because (99m)Tc-MIP-1404 has minimal activity in the bladder, further work is planned to correlate imaging findings with histopathology in patients with high-risk metastatic PCa.
authors.affiliation: New York Presbyterian Hospital and Weill Cornell Medical College, New York, New York svallabh@med.cornell.edu.
authors.forename: Shankar
authors.initials: S
authors.lastname: Vallabhajosula
authors.affiliation: New York Presbyterian Hospital and Weill Cornell Medical College, New York, New York.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nikolopoulou
authors.affiliation: Molecular Insight Pharmaceuticals, Inc., Cambridge, Massachusetts; and.
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
authors.affiliation: New York Presbyterian Hospital and Weill Cornell Medical College, New York, New York.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Osborne
authors.affiliation: New York Presbyterian Hospital and Weill Cornell Medical College, New York, New York.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Tagawa
authors.affiliation: New York Presbyterian Hospital and Weill Cornell Medical College, New York, New York.
authors.forename: Irina
authors.initials: I
authors.lastname: Lipai
authors.affiliation: New York Presbyterian Hospital and Weill Cornell Medical College, New York, New York.
authors.forename: Lilja
authors.initials: L
authors.lastname: Solnes
authors.affiliation: Molecular Insight Pharmaceuticals, Inc., Cambridge, Massachusetts; and.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Maresca
authors.affiliation: Molecular Insight Pharmaceuticals, Inc., Cambridge, Massachusetts; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Armor
authors.affiliation: Molecular Insight Pharmaceuticals, Inc., Cambridge, Massachusetts; and.
authors.forename: John L
authors.initials: JL
authors.lastname: Joyal
authors.affiliation: Molecular Insight Pharmaceuticals, Inc., Cambridge, Massachusetts; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Crummet
authors.affiliation: Radiation Dosimetry Systems, Inc, Alpharetta, Georgia.
authors.forename: James B
authors.initials: JB
authors.lastname: Stubbs
authors.affiliation: New York Presbyterian Hospital and Weill Cornell Medical College, New York, New York.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Goldsmith
mesh_terms: D000368:Aged; D000954:Antigens, Surface / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D015972:Gene Expression Regulation, Neoplastic; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics*; D061214:Patient Safety; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011874:Radiometry; D011877:Radionuclide Imaging / Q000379:methods; D019275:Radiopharmaceuticals; D013667:Technetium / Q000493:pharmacokinetics*; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome; D051598:Whole Body Imaging
chemical_list: D000954:Antigens, Surface; D000970:Antineoplastic Agents; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C000595576:technetium 99m 1-(1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)-9,14-dioxo-2,8,13,15-tetraazaoctadecane-7,12,16,18-tetracarboxylic acid); C000595577:technetium 99m 7-amino-1-(1-(carboxymethyl)-1H-imidazol-2-yl)-2-((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylic acid); D013667:Technetium; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: 99mTc-MIP-1404; 99mTc-MIP-1405; molecular imaging; prostate cancer; prostate specific membrane antigen