Comparison of PSMA-TO-1 and PSMA-617 labeled with gallium-68, lutetium-177 and actinium-225

Catherine Meyer, Vikas Prasad, Andreea Stuparu, Peter Kletting, Gerhard Glatting, Jonathan Miksch, Christoph Solbach, Katharina Lueckerath, Lea Nyiranshuti, Shaojun Zhu, Johannes Czernin, Ambros J. Beer, Roger Slavik, Jeremie Calais, Magnus Dahlbom

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Background: PSMA-TO-1 (“Tumor-Optimized-1”) is a novel PSMA ligand with longer circulation time than PSMA-617. We compared the biodistribution in subcutaneous tumor-bearing mice of PSMA-TO-1, PSMA-617 and PSMA-11 when labeled with 68Ga and 177Lu, and the survival after treatment with 225Ac-PSMA-TO-1/-617 in a murine model of disseminated prostate cancer. We also report dosimetry data of 177Lu-PSMA-TO1/-617 in prostate cancer patients. Methods: First, PET images of 68Ga-PSMA-TO-1/-617/-11 were acquired on consecutive days in three mice bearing subcutaneous C4-2 xenografts. Second, 50 subcutaneous tumor-bearing mice received either 30 MBq of 177Lu-PSMA-617 or 177Lu-PSMA-TO-1 and were sacrificed at 1, 4, 24, 48 and 168 h for ex vivo gamma counting and biodistribution. Third, mice bearing disseminated lesions via intracardiac inoculation were treated with either 40 kBq of 225Ac-PSMA-617, 225Ac-PSMA-TO-1, or remained untreated and followed for survival. Additionally, 3 metastatic castration-resistant prostate cancer patients received 500 MBq of 177Lu-PSMA-TO-1 under compassionate use for dosimetry purposes. Planar images with an additional SPECT/CT acquisition were acquired for dosimetry calculations. Results: Tumor uptake measured by PET imaging of 68Ga-labeled agents in mice was highest using PSMA-617, followed by PSMA-TO-1 and PSMA-11. 177Lu-PSMA tumor uptake measured by ex vivo gamma counting at subsequent time points tended to be greater for PSMA-TO-1 up to 1 week following treatment (p > 0.13 at all time points). This was, however, accompanied by increased kidney uptake and a 26-fold higher kidney dose of PSMA-TO-1 compared with PSMA-617 in mice. Mice treated with a single-cycle 225Ac-PSMA-TO-1 survived longer than those treated with 225Ac-PSMA-617 and untreated mice, respectively (17.8, 14.5 and 7.7 weeks, respectively; p < 0.0001). Kidney, salivary gland, bone marrow and mean ± SD tumor dose coefficients (Gy/GBq) for 177Lu-PSMA-TO-1 in patients #01/#02/#03 were 2.5/2.4/3.0, 1.0/2.5/2.3, 0.14/0.11/0.10 and 0.42 ± 0.03/4.45 ± 0.07/1.8 ± 0.57, respectively. Conclusions: PSMA-TO-1 tumor uptake tended to be greater than that of PSMA-617 in both preclinical and clinical settings. Mice treated with 225Ac-PSMA-TO-1 conferred a significant survival benefit compared to 225Ac-PSMA-617 despite the accompanying increased kidney uptake. In humans, PSMA-TO-1 dosimetry estimates suggest increased tumor absorbed doses; however, the kidneys, salivary glands and bone marrow are also exposed to higher radiation doses. Thus, additional preclinical studies are needed before further clinical use.

Original languageEnglish
Article number65
JournalEJNMMI Research
Issue number1
StatePublished - 2022


  • Dosimetry
  • PSMA-617
  • PSMA-TO-1
  • Prostate cancer
  • Radioligand therapy


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