In vivo evaluation of two tissue transglutaminase PET tracers in an orthotopic tumour xenograft model

Abstract

Background

The protein cross-linking enzyme tissue transglutaminase (TG2; EC 2.3.2.13) is associated with the pathogenesis of various diseases, including cancer. Recently, the synthesis and initial evaluation of two high-potential radiolabelled irreversible TG2 inhibitors were reported by us. In the present study, these two compounds were evaluated further in a breast cancer (MDA-MB-231) tumour xenograft model for imaging active tissue transglutaminase in vivo.

Results

The metabolic stability of [¹¹C]1 and [¹⁸F]2 in SCID mice was comparable to the previously reported stability in Wistar rats. Quantitative real-time polymerase chain reaction analysis on MDA-MB-231 cells and isolated tumours showed a high level of TG2 expression with very low expression of other transglutaminases. PET imaging showed low tumour uptake of [¹¹C]1 (approx. 0.5 percentage of the injected dose per gram (%ID/g) at 40–60 min p.i.) and with relatively fast washout. Tumour uptake for [¹⁸F]2 was steadily increasing over time (approx. 1.7 %ID/g at 40–60 min p.i.). Pretreatment of the animals with the TG2 inhibitor ERW1041E resulted in lower tumour activity concentrations, and this inhibitory effect was enhanced using unlabelled 2.

Conclusions

Whereas the TG2 targeting potential of [¹¹C]1 in this model seems inadequate, targeting of TG2 using [¹⁸F]2 was achieved. As such, [¹⁸F]2 could be used in future studies to clarify the role of active tissue transglutaminase in disease.

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