PET imaging of the anticancer drug candidate [¹¹C]trimebutine in a rat glioma model

Purpose: Preclinical studies suggest that trimebutine could be a potential treatment for glioblastoma. The aim of this study was to investigate the distribution, kinetics and tumor accumulation of [¹¹C]trimebutine.

Method: A proliferation assay and cell scratch healing assay were performed to confirm the antitumor effects of trimebutine on C6 glioma cells in-vitro. Trimebutine was subsequently labeled with ¹¹C. The distribution and kinetics of [¹¹C]trimebutine in health rats and rats with an orthotopic C6 glioma were evaluated by ex-vivo gamma counting and positron emission tomography, respectively. Blocking experiments with an excess of unlabeled trimebutine or the μ-opioid receptor ligand cyprodime were employed to determine if trimebutine exhibits saturable binding in the brain. In addition, plasma stability of the tracer was assessed.

Results: The proliferation assay and cell scratch healing assay confirmed that trimebutine has anti-tumor effects in-vitro. [¹¹C]Trimebutine with a radiochemical purity >98 % was synthesized in 15 ± 5 % radiochemical yield. In peripheral organs, the highest accumulation of the tracer was detected in excretion organs. In the brain, the highest tracer uptake was observed in the brainstem and the lowest in the hypothalamus, although differences between regions were small. PET imaging showed rapid brain uptake of [¹¹C]trimebutine, followed by a gradual washout. Administration of an intravenous dose of trimebutine (10 mg/kg) significantly decreased the uptake in all brain regions (p < 0.05), except midbrain. Likewise, administration of cyprodime (2 mg/kg) significantly reduced [¹¹C]trimebutine uptake in the brain (p < 0.01). However, uptake of [¹¹C]trimebutine in the tumor was not significantly different from its brain uptake in rats bearing an orthotopic C6 glioma. The percentage of intact [¹¹C]trimebutine at 60 min post injection was only 1.7 ± 0.6 %.

Conclusion: Trimebutine exhibits inhibitory effects on the growth and migration of glioma cells in a dose- and time-dependent manner. [¹¹C]Trimebutine was able to penetrate the blood-brain barrier in rats and tracer uptake could be significantly reduced by administration of a μ-opioid receptor antagonist. However, [¹¹C]trimebutine failed to selectively accumulate in orthotopic C6 glioma, which could be caused by low expression levels of the drug target in these tumors, or by fast metabolism of the tracer.