Development of [F]DASA-10 for enhanced imaging of pyruvate kinase M2.

Purpose: The aim of this study was to develop a positron emission tomography (PET) radiotracer for measuring pyruvate kinase M2 (PKM2) with improved physicochemical and pharmacokinetic properties compared to [F]DASA-23.

Experimental Design: First, we synthesized [F]DASA-10 and tested its uptake and retention compared to [F]DASA-23 in human and mouse glioma cell lines. We then confirmed the specificity of [F]DASA-10 by transiently modulating the expression of PKM2 in DU145 and HeLa cells. Next, we determined [F]DASA-10 pharmacokinetics in healthy nude mice using PET imaging and subsequently assessed the ability of [F]DASA-10 versus [F]DASA-23 to enable in vivo detection of intracranial gliomas in syngeneic C6 rat models of glioma.

Results: [F]DASA-10 demonstrated excellent cellular uptake and retention with values significantly higher than [F]DASA-23 in all cell lines and timepoints investigated. [F]DASA-10 showed a 73 % and 65 % reduced uptake respectively in DU145 and HeLa cells treated with PKM2 siRNA as compared to control siRNA treated cells. [F]DASA-10 showed favorable biodistribution and pharmacokinetic properties and a significantly improved tumor-to-brain ratio in rat C6 glioma models relative to [F]DASA-23 (3.2 ± 0.8 versus 1.6 ± 0.3, p = 0.01).

Conclusion: [F]DASA-10 is a new PET radiotracer for molecular imaging of PKM2 with potential to overcome the prior limitations observed with [F]DASA-23. [F]DASA-10 shows promise for clinical translation to enable imaging of brain malignancies owing to its low background signal in the healthy brain.