# Article Review: Comparison of 64Cu DOTA PSMA 3Q and 64Cu NOTA PSMA 3Q utilizing NOTA and DOTA as bifunctional chelators in prostate cancer preclinical assessment and preliminary clinical PET CT imaging

# Objectives
- Compared the efficacy and safety of 64Cu-labeled PSMA-3Q using NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) as bifunctional chelating agents (BFCAs) in prostate cancer.
- Evaluated the stability, bioavailability, and therapeutic potential of 64Cu-DOTA-PSMA-3Q and 64Cu-NOTA-PSMA-3Q in preclinical models and initial clinical trials.

# Methodology
- 64Cu-DOTA-PSMA-3Q and 64Cu-NOTA-PSMA-3Q were synthesized by manual labeling.
- Radiochemical purity, stability, specificity, and biodistribution were evaluated in preclinical studies.
- PET/CT imaging was used in 23 patients with suspected prostate cancer to evaluate the biodistribution of the tracers.
- Statistical analyses included independent sample t-tests, tests for homogeneity of variance, and the Wilcoxon rank sum test.

# Results
- Radiochemical purities of both tracers were >98%.
- Biodistribution in mice: 64Cu-DOTA-PSMA-3Q had significantly higher liver uptake than 64Cu-NOTA-PSMA-3Q at 1h (2.92±0.44% ID/g vs. 0.83±0.06% ID/g, P=0.027).
- Micro-PET/CT in mice: 64Cu-DOTA-PSMA-3Q had better tumor retention at 24h (10.05±0.46% ID/g vs 5.38±1.06%ID/g, P=0.002). ![](https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00259-025-07131-3/MediaObjects/259_2025_7131_Fig1_HTML.png)
- Clinical PET/CT: Liver uptake of 64Cu-NOTA-PSMA-3Q was significantly lower than 64Cu-DOTA-PSMA-3Q (4.04 vs. 8.18). ![](https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00259-025-07131-3/MediaObjects/259_2025_7131_Fig2_HTML.png) ![](https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00259-025-07131-3/MediaObjects/259_2025_7131_Fig3_HTML.png)
- Clinical PET/CT: 64Cu-NOTA-PSMA-3Q had higher uptake in lacrimal glands (17.73 vs. 10.84), parotid glands (20.98 vs. 16.30), and submandibular glands (20.26 vs. 17.28).

# Discussions
- The study is limited by its small sample size (n=23), which may affect the generalizability of the findings. A larger study is needed to confirm these results.
- The lack of biodistribution data from healthy volunteers is a limitation.  Including healthy controls would provide a baseline for comparison.
- While the study compares DOTA and NOTA, it doesn't explore other potential chelators or modifications to the PSMA-3Q ligand that might further improve imaging characteristics.
- The study focuses primarily on biodistribution and imaging. Further investigation into the potential therapeutic applications, especially considering the theranostic potential of 64Cu, would strengthen the study.

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Reference: [Comparison of 64Cu DOTA PSMA 3Q and 64Cu NOTA PSMA 3Q utilizing NOTA and DOTA as bifunctional chelators in prostate cancer preclinical assessment and preliminary clinical PET CT imaging](https://link.springer.com/article/10.1007/s00259-025-07131-3)