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

Abstract

PurposeThe 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@SUPPY.MethodsRats were injected with [18F]FE@SUPPY for baseline scans and blocking scans (A3R with MRS1523 or FE@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@SUPPY and [18F]FDG. Dynamic PET imaging was performed (60 min in rats, 90 min in xenografted mice). In vitro stability of [18F]FE@SUPPY in human and rat plasma was also evaluated.Results[18F]FE@SUPPY showed high uptake in fat-rich regions and low uptake in the brain. Pretreatment with MRS1523 led to a decrease in [18F]FE@SUPPY uptake (p = 0.03), and pretreatment with the P-gp inhibitor tariquidar led to a 1.24-fold increase in [18F]FE@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@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@SUPPY in the tissue masses from CHO cells expressing the human A3R (p = 0.03). [18F]FE@SUPPY was stable in human plasma.ConclusionSelective and significant tracer uptake of [18F]FE@SUPPY was found in xenografted mice injected with cells expressing human A3R. This finding supports the strategy of evaluating [18F]FE@SUPPY in “humanized animal models”. In conclusion, preclinical evaluation points to the suitability of [18F]FE@SUPPY as an A3R PET tracer in humans.

Preclinical In Vitro and In Vivo Evaluation of [18F]FE@SUPPY for Cancer PET Imaging: Limitations of a Xenograft Model for Colorectal Cancer

“…Ex vivo blood stability analysis demonstrated more rapid degradation of [ 18 F]FE@SUPPY in vivo than that observed in in vitro testing as only 2.2 ± 0.4% intact [ 18 F]FE@SUPPY could be determined after 70 min ( Figure 4 ). This data indicates higher metabolism in mice compared to rats described in previously conducted studies, where 25.8 ± 5.3% intact tracer was found in plasma after 60 min [ 22 ]. However, these data could also be mimicked by the fact that intact [ 18 F]FE@SUPPY is rapidly cleared from blood hepatobiliary (into the bile fluid, compare Figures 5 and 7 ), and the equilibrium in blood is therefore shifted to the metabolites.…”

“…Blood samples were collected and immediately precipitated using acetonitrile/methanol (10 : 1) and centrifuged (12,000 rpm, 5 min, 4°C). The obtained supernatants were subjected to radio-HPLC as previously described [ 22 ].…”

“…The A 3 AR antagonist [ 18 F]FE@SUPPY has been presented as the first PET-tracer for hA 3 AR imaging in 2008 by Wadsak et al [ 20 , 21 ]. First preclinical PET imaging using CHO-K1-hA 3 AR xenografts has shown promising results leading to further evaluation of this PET-tracer in oncology [ 22 ]. Besides [ 18 F]FE@SUPPY and [ 18 F]FE@SUPPY:2, only a few other PET-ligands have been proposed for A 3 AR imaging, including carbon-11 labeled 1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives and bromine-76 labeled nucleoside ligands ([ 76 Br]MRS3581 and [ 76 Br]MRS5147) [ 23 – 25 ].…”