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Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment
Published on: April 25, 2025
68Ga-labeled ODAP-Urea-based PSMA agents in prostate cancer: first-in-human imaging of an optimized agent
Xiaojiang Duan1, Zhen Cao1, Hua Zhu2
1Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China.
Purpose:
Prostate-specific membrane antigen (PSMA) is a promising target for prostate cancer imaging and therapy. The most commonly used scaffold incorporates a glutamate-urea (Glu-Urea) function. We recently developed oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA ligands in an attempt to improve upon the pharmacokinetic properties of existing agents. Here, we report the synthesis of an optimized 68Ga-labeled ODAP-Urea-based ligand, [68Ga]Ga-P137, and first-in-human results.
Methods:
Twelve ODAP-Urea-based ligands were synthesized and radiolabeled with 68Ga in high radiochemical yield and purity. Their PSMA inhibitory capacities were determined using the NAALADase assay. Radioligands were evaluated in mice-bearing 22Rv1 prostate tumors by microPET. Lead compound [68Ga]Ga-P137 was evaluated for stability, cell uptake, and biodistribution. PET imaging of [68Ga]Ga-P137 was performed in three patients head-to-head compared to [68Ga]Ga-PSMA-617.
Results:
Ligands were synthesized in 11.1-44.4% yield and > 95% purity. They have high affinity to PSMA (Ki of 0.13 to 5.47 nM). [68Ga]Ga-P137 was stable and hydrophilic. [68Ga]Ga-P137 showed higher uptake than [68Ga]Ga-PSMA-617 in tumor-bearing mice at 6.43 ± 0.98%IA/g vs 3.41 ± 1.31%IA/g at 60-min post-injection. In human studies, the normal organ biodistribution of [68Ga]Ga-P137 was grossly equivalent to that of [68Ga]Ga-PSMA-617 except for within the urinary tract, in which [68Ga]Ga-P137 demonstrated lower uptake.
Conclusion:
The optimized ODAP-Urea-based ligand [68Ga]Ga-P137 can image PSMA in xenograft models and humans, with lower bladder accumulation to the Glu-Urea-based agent, [68Ga]Ga-PSMA-617, in a preliminary, first-in-human study.
Trial Registration:
ClinicalTrials.gov Identifier: NCT04560725, Registered 23 September 2020. https://clinicaltrials.gov/ct2/show/NCT04560725.
Insights
A new Gallium-68 labeled oxalyldiaminopropionic acid-urea (ODAP-Urea) ligand, [68Ga]Ga-P137, shows promise for prostate cancer imaging. This agent demonstrated lower urinary tract accumulation compared to existing PSMA-targeting agents in early human studies.
Area of Science:
- Nuclear Medicine
- Radiopharmaceutical Chemistry
- Oncology
Background:
- Prostate-specific membrane antigen (PSMA) is a key target for prostate cancer diagnostics and therapeutics.
- Current PSMA-targeting agents often utilize a glutamate-urea (Glu-Urea) scaffold.
- Oxalyldiaminopropionic acid-urea (ODAP-Urea) ligands were developed to potentially improve pharmacokinetic properties.
Purpose of the Study:
- To synthesize and characterize an optimized Gallium-68 (68Ga)-labeled ODAP-Urea-based ligand, designated [68Ga]Ga-P137.
- To evaluate the in vivo performance of [68Ga]Ga-P137 in preclinical models and in a first-in-human study.
- To compare the imaging characteristics of [68Ga]Ga-P137 with a clinically used PSMA agent, [68Ga]Ga-PSMA-617.
Main Methods:
- Synthesis and radiolabeling of twelve ODAP-Urea-based ligands with 68Ga.
- Assessment of PSMA inhibitory capacity using the NAALADase assay.
- Preclinical evaluation in 22Rv1 prostate tumor-bearing mice using microPET imaging.
- First-in-human PET imaging of [68Ga]Ga-P137 in three patients, compared head-to-head with [68Ga]Ga-PSMA-617.
Main Results:
- Synthesized ligands exhibited high PSMA affinity (Ki 0.13–5.47 nM) and were labeled with high radiochemical purity (>95%).
- [68Ga]Ga-P137 demonstrated favorable stability and hydrophilicity.
- In mice, [68Ga]Ga-P137 showed significantly higher tumor uptake compared to [68Ga]Ga-PSMA-617.
- Human studies revealed comparable normal organ biodistribution, but notably lower urinary tract accumulation for [68Ga]Ga-P137.
Conclusions:
- The optimized ODAP-Urea-based ligand [68Ga]Ga-P137 is capable of imaging PSMA in both xenograft models and humans.
- Preliminary first-in-human data suggest [68Ga]Ga-P137 offers an advantage over the Glu-Urea-based agent [68Ga]Ga-PSMA-617 due to reduced bladder accumulation.
- Further investigation of [68Ga]Ga-P137 for prostate cancer imaging and therapy is warranted.
