PSMA-1-DOTA Potentially for Effective Targeted Radioligand Therapy of Prostate Cancer

  • Mol Imaging Biol. 2025 Sep 2. doi: 10.1007/s11307-025-02046-9.
Xinning Wang  1 ,  Olga Sergeeva  2 ,  Maxim Sergeev  3 ,  Lifang Zhang  1 ,  Zoey Lockwood  3 ,  Patrick Wojtylak  4 ,  Riley Sangster  5 ,  David Reichert  5 ,  Marc Berridge  5 ,  Wolfgang Weber  6 ,  Zhenghong Lee  7  8  9 ,  James P Basilion  10  11
Affiliations
  • 1. Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.
  • 2. Radiology, Case Western Reserve University, Cleveland, OH, USA.
  • 3. Chemistry, Case Western Reserve University, Cleveland, OH, USA.
  • 4. Nuclear Medicine, Radiology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
  • 5. 3D Imaging, LCC, Little Rock, AR, USA.
  • 6. Klinikum Rechts Der Isar, Nuklearmedizin, Technische Universität München (TUM), München, Germany.
  • 7. Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA. [email protected].
  • 8. Radiology, Case Western Reserve University, Cleveland, OH, USA. [email protected].
  • 9. Chemistry, Case Western Reserve University, Cleveland, OH, USA. [email protected].
  • 10. Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA. [email protected].
  • 11. Radiology, Case Western Reserve University, Cleveland, OH, USA. [email protected].
PMID: 40897948 DOI: 10.1007/s11307-025-02046-9
Abstract

Purpose: While PSMA-targeted radioligand therapy (RLT) has shown remarkable efficacy for treating end-stage prostate Cancer, the α-emitting RLT often results in severe salivary gland toxicity, limiting its use. Various strategies to mitigate this side effect have been attempted with limited success. Accordingly, this study introduced a new PSMA-targeting ligand with more favorable binding characteristics than the existing ligands.

Procedures: The binding affinity of PSMA-1-DOTA to PSMA was compared with that of PSMA-11 and PSMA I&T. Comparison of uptake in the salivary glands, kidneys and PC3pip tumor cells in the xenograft mouse models between [68 Ga]Ga-PSMA-1-DOTA, [68 Ga]Ga-PSMA-11 and [68 Ga]Ga-PSMA I&T was conducted with microPET/CT within the same week. The same mouse models were treated with [177Lu]Lu-PSMA-1-DOTA or [177Lu]Lu-PSMA-617. A compassionate use PET imaging study on a patient with metastatic castration-resistant prostate Cancer was performed using [68 Ga]Ga-PSMA-1-DOTA.

Results: The binding affinity of PSMA-1-DOTA to PSMA was found to be approximately four times greater than Other PSMA-targeted ligands. Imaging with microPET/CT revealed significantly lower kidney, uptake and little salivary and lacrimal gland uptake with [68 Ga]Ga-PSMA-1-DOTA compared to Other PSMA-radioligands. Preclinical efficacy studies demonstrated that [177Lu]Lu-PSMA-1-DOTA inhibited tumor growth comparable to that with [177Lu]Lu-PSMA-617, suggesting its potential to enhance the therapeutic window of targeted RLT by avoiding damage to the salivary glands. The compassionate use PET imaging confirmed the reduced salivary gland uptake of [68 Ga]Ga-PSMA-1-DOTA in the patient, indicating its potential utility as a targeting agent for RLT with α- or β-emitting radionuclides in patients with PSMA-positive prostate Cancer.

Conclusion: PSMA-1-DOTA shows reduced uptake in salivary glands while effectively targeting PSMA-expressing tumors, thus potentially avoiding the side effects of xerostomia, and possibly moving PSMA-targeted RLT to a more frontline therapy for prostate Cancer rather than the current use as a last resort.

Keywords
Dry mouth; PSMA; Prostate cancer; Targeted radioligand therapy.
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