[¹⁸F]FE rate at SUPPY: a suitable PET tracer for the adenosine A3 receptor? An in vivo study in rodents

The adenosine A₃ receptor (A3R) is involved in cardiovascular, neurological and tumour-related pathologies and serves as an exceptional pharmaceutical target in the clinical setting. A3R antagonists are considered antiinflammatory, antiallergic and anticancer agents, and to have potential for the treatment of asthma, COPD, glaucoma and stroke. Hence, an appropriate A3R PET tracer would be highly beneficial for the diagnosis and therapy monitoring of these diseases. Therefore, in this preclinical in vivo study we evaluated the potential as a PET tracer of the A3R antagonist [¹⁸F]FE rate at SUPPY. Rats were injected with [¹⁸F]FE rate at SUPPY for baseline scans and blocking scans (A3R with MRS1523 or FE rate at SUPPY, P-gp with tariquidar; three animals each). Additionally, metabolism was studied in plasma and brain. In a preliminary experiment in a mouse xenograft model (mice injected with cells expressing the human A3R; three animals), the animals received [¹⁸F]FE rate at SUPPY and [¹⁸F]FDG. Dynamic PET imaging was performed (60 min in rats, 90 min in xenografted mice). In vitro stability of [¹⁸F]FE rate at SUPPY in human and rat plasma was also evaluated. [¹⁸F]FE rate at SUPPY showed high uptake in fat-rich regions and low uptake in the brain. Pretreatment with MRS1523 led to a decrease in [¹⁸F]FE rate at SUPPY uptake (p = 0.03), and pretreatment with the P-gp inhibitor tariquidar led to a 1.24-fold increase in [¹⁸F]FE rate at SUPPY uptake (p = 0.09) in rat brain. There was no significant difference in metabolites in plasma and brain in the treatment groups. However, plasma concentrations of [¹⁸F]FE rate at SUPPY were reduced to levels similar to those in rat brain after blocking. In contrast to [¹⁸F]FDG uptake (p = 0.12), the xenograft model showed significantly increased uptake of [¹⁸F]FE rate at SUPPY in the tissue masses from CHO cells expressing the human A3R (p = 0.03). [¹⁸F]FE rate at SUPPY was stable in human plasma. Selective and significant tracer uptake of [¹⁸F]FE rate at SUPPY was found in xenografted mice injected with cells expressing human A3R. This finding supports the strategy of evaluating [¹⁸F]FE rate at SUPPY in ''humanized animal models''. In conclusion, preclinical evaluation points to the suitability of [¹⁸F]FE rate at SUPPY as an A3R PET tracer in humans. (orig.)