Validation of ⁶⁸Ga-4HMSA-PSMA, a novel PSMA radioligand for PET Imaging of Prostate Cancer

Objectives: Prostate cancer (PCa) is known to be the second most commonly occurring cancer in men. In 2018, there were around 1.3 million new cases diagnosed around the world. New specific ⁶⁸Ga-PSMA PET tracers have the ability to non-invasively discriminate adenocarcinomas offering new tools for visualizing PCa. Recently our group has developed a new chelator with four N-hydroxy-N-methyl succinamide pendant arms (4HMSA) that forms a strong complex with Ga(III). The aim of this project was to assess for the first time the suitability of [⁶⁸Ga]Ga-4HMSA-PSMA for visualizing protaste tumor by PET imaging. A comparative study with existing [⁶⁸Ga]Ga-DOTA-PSMA (PSMA-617) was performed in order to outline the full potential of our novel PET tracer.

Methods: Both peptides were synthetized on solid phase and labelled with cyclotron produced ⁶⁸Ga. Biodistribution of radiolabeled peptides was performed on female balb/c mice, sacrificed at different time points between 15 and 120 min. A blocking group received 20 nmol of PMPA and was sacrificed at 60 min post-injection. Finally, µPET imaging was performed on female athymic nude mice bearing LN-CaP tumors for 60 minutes with or without 20 nmol of PMPA.

Results: Both PSMA radioligands were prepared with yields >95% using cyclotron-produced ⁶⁸Ga. By contrast with DOTA-PSMA, radiolabelling of 4HMSA-PSMA was achieved in less than 5 minutes at room temperature. [⁶⁸Ga]Ga-DOTA-PSMA and [⁶⁸Ga]Ga-4HSMA-PSMA showed similar affinity (2.1 and 3.7 nM, respectively) in PCa cells. Kidney uptake of ⁶⁸Ga-4HMSA-PSMA is specific (2-PMPA blockade, P= 0.001) and lower than that of [⁶⁸Ga]Ga-DOTA-PSMA at 1h after injection. Moreover, the µPET imaging showed a higher tumor uptake and a better blockade for the [⁶⁸Ga]Ga-4HMSA-PSMA at every time point.

Conclusions: [⁶⁸Ga]Ga -4HMSA-PSMA allows visualization of prostate tumors by PET imaging. 4HMSA enables fast [⁶⁸Ga]Ga chelation under mild condition, and as such could be used advantageously for the development of other ⁶⁸Ga-labeled peptide-derived PET tracers.

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