title: 68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies.
abstract: On the basis of the high and consistent expression of prostate-specific membrane antigen (PSMA) in metastatic prostate cancer (PC), the goal of this study was the development, preclinical evaluation, and first proof-of-concept investigation of a PSMA inhibitor for imaging and therapy (PSMA I&T) for (68)Ga-based PET and (177)Lu-based endoradiotherapeutic treatment in patients with metastatic and castration-resistant disease.
  
  
  METHODS
  PSMA I&T was synthesized in a combined solid phase and solution chemistry strategy. The PSMA affinity of (nat)Ga-/(nat)Lu-PSMA I&T was determined in a competitive binding assay using LNCaP cells. Internalization kinetics of (68)Ga- and (177)Lu-PSMA I&T were investigated using the same cell line, and biodistribution studies were performed in LNCaP tumor-bearing CD-1 nu/nu mice. Initial human PET imaging studies using (68)Ga-PSMA I&T, as well as endoradiotherapeutic treatment of 2 patients with metastatic PC using (177)Lu-PSMA I&T, were performed.
  
  
  RESULTS
  PSMA I&T and its cold gallium and lutetium analog revealed nanomolar affinity toward PSMA. The DOTAGA (1,4,7,10-tetraazacyclododecane-1-(glutamic acid)-4,7,10-triacetic acid) conjugate PSMA I&T allowed fast and high-yield labeling with (68)Ga(III) and (177)Lu(III). Uptake of (68)Ga-/(177)Lu-PSMA I&T in LNCaP tumor cells is highly efficient and PSMA-specific, as demonstrated by competition studies both in vitro and in vivo. Tumor targeting and tracer kinetics in vivo were fast, with the highest uptake in tumor xenografts and kidneys (both PSMA-specific). First-in-human (68)Ga-PSMA I&T PET imaging allowed high-contrast detection of bone lesions, lymph node, and liver metastases. Endoradiotherapy with (177)Lu-PSMA I&T in 2 patients was found to be effective and safe with no detectable side effects.
  
  
  CONCLUSIONS
  (68)Ga-PSMA I&T shows potential for high-contrast PET imaging of metastatic PC, whereas its (177)Lu-labeled counterpart exhibits suitable targeting and retention characteristics for successful endoradiotherapeutic treatment. Prospective studies on larger cohorts of patients are warranted and planned.
authors.affiliation: Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany martina.weineisen@tum.de.
authors.forename: Martina
authors.initials: M
authors.lastname: Weineisen
authors.affiliation: Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany.
authors.forename: Margret
authors.initials: M
authors.lastname: Schottelius
authors.affiliation: Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany Scintomics GmbH, Fürstenfeldbruck, Germany.
authors.forename: Jakub
authors.initials: J
authors.lastname: Simecek
authors.affiliation: Theranostics Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), Zentralklinik Bad Berka, Bad Berka, Germany.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Baum
authors.affiliation: Department of Nuclear Medicine, Medstar Hospital Cancer Center, Antalya, Turkey.
authors.forename: Akin
authors.initials: A
authors.lastname: Yildiz
authors.affiliation: Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany; and.
authors.forename: Seval
authors.initials: S
authors.lastname: Beykan
authors.affiliation: Theranostics Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), Zentralklinik Bad Berka, Bad Berka, Germany.
authors.forename: Harshad R
authors.initials: HR
authors.lastname: Kulkarni
authors.affiliation: Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Lassmann
authors.affiliation: Theranostics Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), Zentralklinik Bad Berka, Bad Berka, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Klette
authors.affiliation: Department of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eiber
authors.affiliation: Department of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.affiliation: Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
mesh_terms: D000368:Aged; D000812:Anhydrides / Q000737:chemistry; D000818:Animals; D000954:Antigens, Surface; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry; D056831:Coordination Complexes / Q000737:chemistry*; D005260:Female; D005710:Gallium Radioisotopes; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008187:Lutetium; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000737:chemistry*; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D011874:Radiometry; D011878:Radiotherapy
chemical_list: C000615601:68Ga-DOTAGA-(3-iodo-y)fk(Sub-KuE); D000812:Anhydrides; D000954:Antigens, Surface; D003287:Contrast Media; D056831:Coordination Complexes; C574967:DOTAGA-anhydride; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D009842:Oligopeptides; D008187:Lutetium; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: 177Lu; 68Ga; PSMA I&T; prostate cancer; prostate-specific membrane antigen