title: (R)-NODAGA-PSMA: A Versatile Precursor for Radiometal Labeling and Nuclear Imaging of PSMA-Positive Tumors.
abstract: OBJECTIVE
  The present study aims at developing and evaluating an urea-based prostate specific membrane antigen (PSMA) inhibitor suitable for labeling with 111In for SPECT and intraoperative applications as well as 68Ga and 64Cu for PET imaging.
  
  
  METHODS
  The PSMA-based inhibitor-lysine-urea-glutamate-coupled to the spacer Phe-Phe-D-Lys(suberoyl) and functionalized with the enantiomerically pure prochelator (R)-1-(1-carboxy-3-carbotertbutoxypropyl)-4,7-carbotartbutoxymethyl)-1,4,7-triazacyclononane ((R)-NODAGA(tBu)3), to obtain (R)-NODAGA-Phe-Phe-D-Lys(suberoyl)-Lys-urea-Glu (CC34). CC34 was labeled with 111In, 68Ga and 64Cu. The radioconjugates were further evaluated in vitro and in vivo in LNCaP xenografts by biodistribution and PET studies. Biodistribution studies were also performed with 68Ga-HBED-CC-PSMA (HBED-CC: N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) and 111In-PSMA-617 for comparison.
  
  
  RESULTS
  68Ga-CC34, 64Cu-CC34, and 111In-CC34 were prepared in radiochemical purity > 95%. 68/natGa-CC34, 64/natCu-CC34, 111/natIn-CC34, 68/natGa-HBED-CC-PSMA, and 111/natIn-PSMA-617 exhibited high affinity for the LNCaP cells, with Kd values of 19.3 ± 2.5 nM, 27.5 ± 2.7 nM, 5.5 ± 0.9 nM, 2.9 ± 0.6 nM and 5.4 ± 0.8 nM, respectively. They revealed comparable internalization profiles with approximately 75% of the total cell associated activity internalized after 3 h of incubation. 68Ga-CC34 showed very high stability after its administration in mice. Tumor uptake of 68Ga-CC34 (14.5 ± 2.9% IA/g) in LNCaP xenografts at 1 h p.i. was comparable to 68Ga-HBED-CC-PSMA (15.8 ± 1.4% IA/g) (P = 0.67). The tumor-to-normal tissue ratios at 1 and 2 h p.i of 68Ga-CC34 were also comparable to 68Ga-HBED-CC-PSMA (P > 0.05). Tumor uptake of 111In-CC34 (28.5 ± 2.6% IA/g) at 1 h p.i. was lower than 111In-PSMA-617 (52.1 ± 6.5% IA/g) (P = 0.02). The acquisition of PET-images with 64Cu-CC34 at later time points showed wash-out from the kidneys, while tumor uptake still remained relatively high. This resulted in an increased tumor-to-kidney ratio over time.
  
  
  CONCLUSIONS
  68Ga-CC34 is comparable to 68Ga-HBED-CC-PSMA in terms of tumor uptake and tumor to normal tissue ratios. 64Cu-CC34 could enable high contrast imaging of PSMA positive tissues characterized by elevated expression of PSMA or when delayed imaging is required. 64Cu-CC34 is currently being prepared for clinical translation.
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.|Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Eleni
authors.initials: E
authors.lastname: Gourni
authors.affiliation: Institut de Chimie Moléculaire de l'Université de Bourgogne, UMR6302, CNRS, University Bourgogne Franche-Comté, Dijon, France.
authors.forename: Coline
authors.initials: C
authors.lastname: Canovas
authors.affiliation: Institut de Chimie Moléculaire de l'Université de Bourgogne, UMR6302, CNRS, University Bourgogne Franche-Comté, Dijon, France.
authors.forename: Victor
authors.initials: V
authors.lastname: Goncalves
authors.affiliation: Institut de Chimie Moléculaire de l'Université de Bourgogne, UMR6302, CNRS, University Bourgogne Franche-Comté, Dijon, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Denat
authors.affiliation: Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Philipp T
authors.initials: PT
authors.lastname: Meyer
authors.affiliation: Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000085:Acetates / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D005260:Female; D005710:Gallium Radioisotopes / Q000493:pharmacokinetics; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C572723:1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane; D000085:Acetates; D000954:Antigens, Surface; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D019275:Radiopharmaceuticals; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II