title: Clinical translation of a PSMA inhibitor for99mTc-based SPECT.
abstract: BACKGROUND
  Prostate-specific membrane antigen (PSMA) is highly over-expressed in advanced prostate cancers.68Ga-labeled PSMA inhibitors (iPSMA) are currently used for prostate cancer detection by PET imaging. The availability of simple, efficient and reproducible radiolabeling procedures is essential for developing new SPECT radiopharmaceuticals for clinical translation. The aim of this research was to prepare99mTc-EDDA/HYNIC-Lys(Nal)-Urea-Glu (99mTc-EDDA/HYNIC-iPSMA) obtained from lyophilized kit formulations and evaluate the in vitro and in vivo radiopharmaceutical binding to prostate cancer cells over-expressing PSMA, as well as the99mTc-EDDA/HYNIC-iPSMA normal biodistribution in humans and the preliminary uptake in patients with prostate cancer.
  
  
  METHODS
  99mTc labeling was performed by adding sodium pertechnetate solution and a 0.2M phosphate buffer (pH 7.0) to a lyophilized formulation containing HYNIC-iPSMA, EDDA, tricine, mannitol and stannous chloride. The radiochemical purity was evaluated by reversed-phase HPLC and ITLC-SG analyses. Stability studies in human serum were performed by size-exclusion HPLC. In vitro cell uptake was tested using prostate cancer cells (LNCaP) with blocked and non-blocked receptors. Biodistribution and tumor uptake were determined in LNCaP tumor-bearing nude mice with blocked and non-blocked receptors, and images were obtained using a micro-SPECT/CT. Whole-body images from three healthy men and two patients with histologically-confirmed prostate cancer (one of them with a previous68Ga-PSMA-617scan) were acquired at 1h and 3h after99mTc-EDDA/HYNIC-iPSMA administration with radiochemical purities of >98%.
  
  
  RESULTS
  In vitro and in vivo studies showed high radiopharmaceutical stability in human serum, specific recognition for PSMA, high tumor uptake (10.22±2.96% ID/g at 1h) with rapid blood clearance and mainly kidney elimination. Preliminary images in patients demonstrated the ability of99mTc-EDDA/HYNIC-iPSMA to detect tumors and metastases of prostate cancer as well as68Ga-PSMA-617 does.
  
  
  CONCLUSIONS
  The results obtained in this study warrant further dosimetry and clinical studies to determine the specificity and sensitivity of99mTc-EDDA/HYNIC-iPSMA.
authors.affiliation: Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac, 52750, Estado de México, Mexico. Electronic address: ferro_flores@yahoo.com.mx.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Ferro-Flores
authors.affiliation: Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac, 52750, Estado de México, Mexico.
authors.forename: Myrna
authors.initials: M
authors.lastname: Luna-Gutiérrez
authors.affiliation: Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac, 52750, Estado de México, Mexico.
authors.forename: Blanca
authors.initials: B
authors.lastname: Ocampo-García
authors.affiliation: Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac, 52750, Estado de México, Mexico.
authors.forename: Clara
authors.initials: C
authors.lastname: Santos-Cuevas
authors.affiliation: Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac, 52750, Estado de México, Mexico.
authors.forename: Erika
authors.initials: E
authors.lastname: Azorín-Vega
authors.affiliation: CONACyT, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac, 52750, Estado de México, Mexico.
authors.forename: Nallely
authors.initials: N
authors.lastname: Jiménez-Mancilla
authors.affiliation: Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac, 52750, Estado de México, Mexico.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Orocio-Rodríguez
authors.affiliation: Departamento de Medicina Nuclear, Instituto Nacional de Cancerología, Ciudad de México, 14000, Mexico.
authors.forename: Jenny
authors.initials: J
authors.lastname: Davanzo
authors.affiliation: Departamento de Medicina Nuclear, Instituto Nacional de Cancerología, Ciudad de México, 14000, Mexico.
authors.forename: Francisco O
authors.initials: FO
authors.lastname: García-Pérez
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000954:Antigens, Surface; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D011854:Radiochemistry; D013667:Technetium; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D057170:Translational Research, Biomedical; D014508:Urea / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000954:Antigens, Surface; D004791:Enzyme Inhibitors; D013667:Technetium; D014508:Urea; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: (99m)Tc-PSMA inhibitor; Clinical translation; HYNIC-PSMA inhibitor; Prostate cancer imaging; SPECT