Synthesis and Evaluation of 68Ga- and 177Lu-Labeled (R)- vs (S)-DOTAGA Prostate-Specific Membrane Antigen-Targeting Derivatives

Mol Pharm. 2020 Dec 7;17(12):4589-4602. doi: 10.1021/acs.molpharmaceut.0c00777. Epub 2020 Oct 27.

Abstract

Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer cells and therefore is an attractive target for prostate cancer diagnosis and radionuclide therapy. Recently, published results from clinical studies using a new PSMA-targeting PET imaging agent, [68Ga]Ga-PSMA-093 ([68Ga]Ga-HBED-CC-O-carboxymethyl-Tyr-CO-NH-Glu), support the development of this agent for the diagnosis of prostate cancer. In this study, the HBED-CC chelating group in PSMA-093 was replaced by stereoselective (R)- or (S)-DOTAGA. This chelating group serves not only for chelating 68Ga but is also amendable for complexing other radioactive metals for radionuclide therapy. The corresponding optically pure (R)- and (S)-[68Ga/177Lu]-DOTAGA derivatives, (R)-[68Ga/177Lu]-13 and (S)-[68Ga/177Lu]-13, were successfully prepared. Comparison of radiolabeling, binding affinity, cell uptake, and biodistribution between the two isomers was performed. Radiolabeling of (R)-[177Lu]Lu-13 and (S)-[177Lu]Lu-13 at 50 °C suggested that rates of complex formation were time-dependent and the formation of (S)-[177Lu]Lu-13 was distinctly faster. The rates of complex formation for the corresponding 68Ga agents were comparable between structural isomers. The natGa and natLu equivalents showed high binding PSMA affinity (IC50 = 24-111 nM), comparable to that of the parent agent, [natGa]Ga-PSMA-093 (IC50 = 34.0 nM). Results of cell uptake and biodistribution studies in PSMA-expressing PC3-PIP tumor-bearing mice appeared to show no difference between the labeled (R)- and (S)-isomers. This is the first time that a pair of [68Ga/177Lu]-(R)- and (S)-DOTAGA isomers of PSMA agents were evaluated. Results of biological studies between the isomers showed no noticeable difference; however, the distinctions on the rate of Lu complex formation should be considered in the development of new 177Lu-DOTAGA-based radionuclide therapy agents in the future.

Keywords: DOTAGA; PSMA; biodistribution; cell uptake; chelating agents; gallium; lutetium; optical isomers; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / metabolism*
  • Cell Line, Tumor
  • Chelating Agents / administration & dosage
  • Chelating Agents / chemical synthesis
  • Chelating Agents / pharmacokinetics
  • Gallium Radioisotopes
  • Glutamate Carboxypeptidase II / metabolism*
  • Humans
  • Inhibitory Concentration 50
  • Lutetium
  • Male
  • Mice
  • Molecular Imaging / methods
  • Molecular Probes / administration & dosage
  • Molecular Probes / chemical synthesis
  • Molecular Probes / pharmacokinetics*
  • Positron-Emission Tomography / methods*
  • Prostatic Neoplasms / diagnostic imaging*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / radiotherapy
  • Radioisotopes
  • Radiopharmaceuticals / administration & dosage
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / pharmacokinetics*
  • Stereoisomerism
  • Tissue Distribution
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, Surface
  • Chelating Agents
  • Gallium Radioisotopes
  • Molecular Probes
  • Radioisotopes
  • Radiopharmaceuticals
  • Lutetium
  • Gallium-68
  • Lutetium-177
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II