title: Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer.
abstract: Despite many advances in the past years, the treatment of metastatic prostate cancer still remains challenging. In recent years, prostate-specific membrane antigen (PSMA) inhibitors were intensively studied to develop low-molecular-weight ligands for imaging prostate cancer lesions by PET or SPECT. However, the endoradiotherapeutic use of these compounds requires optimization with regard to the radionuclide-chelating agent and the linker moiety between chelator and pharmacophore, which influence the overall pharmacokinetic properties of the resulting radioligand. In an effort to realize both detection and optimal treatment of prostate cancer, a tailor-made novel naphthyl-containing DOTA-conjugated PSMA inhibitor has been developed.
  
  
  METHODS
  The peptidomimetic structure was synthesized by solid-phase peptide chemistry and characterized using reversed-phase high-performance liquid chromatography and matrix-assisted laser desorption/ionization mass spectrometry. Subsequent (67/68)Ga and (177)Lu labeling resulted in radiochemical yields of greater than 97% or greater than 99%, respectively. Competitive binding and internalization experiments were performed using the PSMA-positive LNCaP cell line. The in vivo biodistribution and dynamic small-animal PET imaging studies were investigated in BALB/c nu/nu mice bearing LNCaP xenografts.
  
  
  RESULTS
  The chemically modified PSMA inhibitor PSMA-617 demonstrated high radiolytic stability for at least 72 h. A high inhibition potency (equilibrium dissociation constant [K(i)] = 2.34 ± 2.94 nM on LNCaP; K(i) = 0.37 ± 0.21 nM enzymatically determined) and highly efficient internalization into LNCaP cells were demonstrated. The small-animal PET measurements showed high tumor-to-background contrasts as early as 1 h after injection. Organ distribution revealed specific uptake in LNCaP tumors and in the kidneys 1 h after injection. With regard to therapeutic use, the compound exhibited a rapid clearance from the kidneys from 113.3 ± 24.4 at 1 h to 2.13 ± 1.36 percentage injected dose per gram at 24 h. The favorable pharmacokinetics of the molecule led to tumor-to-background ratios of 1,058 (tumor to blood) and 529 (tumor to muscle), respectively, 24 h after injection.
  
  
  CONCLUSIONS
  The tailor-made DOTA-conjugated PSMA inhibitor PSMA-617 presented here is sustainably refined and advanced with respect to its tumor-targeting and pharmacokinetic properties by systematic chemical modification of the linker region. Therefore, this radiotracer is suitable for a first-in-human theranostic application and may help to improve the clinical management of prostate cancer in the future.
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Benešová
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bauder-Wüst
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany; and.
authors.forename: Ali
authors.initials: A
authors.lastname: Afshar-Oromieh
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany; and.
authors.forename: Clemens
authors.initials: C
authors.lastname: Kratochwil
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany; and.
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany; and Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany m.eder@dkfz-heidelberg.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
mesh_terms: D000818:Animals; D000954:Antigens, Surface; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000737:chemistry*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D008187:Lutetium; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry; D049268:Positron-Emission Tomography; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000532:radiotherapy*; D019275:Radiopharmaceuticals; D011878:Radiotherapy; D015203:Reproducibility of Results; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014018:Tissue Distribution
chemical_list: C000610110:Pluvicto; D000954:Antigens, Surface; D002614:Chelating Agents; D004151:Dipeptides; D006573:Heterocyclic Compounds, 1-Ring; C000602389:PSMA-617; D010455:Peptides; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D008187:Lutetium; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen
keywords: PET imaging; PSMA; endoradiotherapy; prostate cancer; theranostic radiopharmaceuticals