Haeusler Daniela, Kuntner Claudia, Nics Lukas, Savli Markus, Zeilinger Markus, Wanek Thomas, Karagiannis Panagiotis, Lanzenberger Rupert R, Langer Oliver, Shanab Karem, Spreitzer Helmut, Wadsak Wolfgang, Hacker Marcus, Mitterhauser Markus
Department of Nuclear Medicine, Medical University of Vienna, 1090, Vienna, Austria.
Eur J Nucl Med Mol Imaging. 2015 Apr;42(5):741-9. doi: 10.1007/s00259-014-2976-3. Epub 2015 Jan 20.
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 [(18)F]FE@SUPPY.
Rats were injected with [(18)F]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 [(18)F]FE@SUPPY and [(18)F]FDG. Dynamic PET imaging was performed (60 min in rats, 90 min in xenografted mice). In vitro stability of [(18)F]FE@SUPPY in human and rat plasma was also evaluated.
[(18)F]FE@SUPPY showed high uptake in fat-rich regions and low uptake in the brain. Pretreatment with MRS1523 led to a decrease in [(18)F]FE@SUPPY uptake (p = 0.03), and pretreatment with the P-gp inhibitor tariquidar led to a 1.24-fold increase in [(18)F]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 [(18)F]FE@SUPPY were reduced to levels similar to those in rat brain after blocking. In contrast to [(18)F]FDG uptake (p = 0.12), the xenograft model showed significantly increased uptake of [(18)F]FE@SUPPY in the tissue masses from CHO cells expressing the human A3R (p = 0.03). [(18)F]FE@SUPPY was stable in human plasma.
Selective and significant tracer uptake of [(18)F]FE@SUPPY was found in xenografted mice injected with cells expressing human A3R. This finding supports the strategy of evaluating [(18)F]FE@SUPPY in "humanized animal models". In conclusion, preclinical evaluation points to the suitability of [(18)F]FE@SUPPY as an A3R PET tracer in humans.
腺苷A3受体（A3R）参与心血管、神经和肿瘤相关的病理过程，是临床环境中一个特殊的药物靶点。A3R拮抗剂被认为具有抗炎、抗过敏和抗癌作用，有治疗哮喘、慢性阻塞性肺疾病（COPD）、青光眼和中风的潜力。因此，一种合适的A3R正电子发射断层显像（PET）示踪剂对这些疾病的诊断和治疗监测将非常有益。所以，在这项临床前体内研究中，我们评估了A3R拮抗剂[(18)F]FE@SUPPY作为PET示踪剂的潜力。
给大鼠注射[(18)F]FE@SUPPY进行基线扫描和阻断扫描（用MRS1523或FE@SUPPY阻断A3R，用 tariquidar阻断P-糖蛋白；每组三只动物）。此外，研究了其在血浆和脑中的代谢情况。在一个小鼠异种移植模型的初步实验中（给小鼠注射表达人A3R的细胞；三只动物），动物接受[(18)F]FE@SUPPY和[(18)F]氟代脱氧葡萄糖（FDG）。进行了动态PET成像（大鼠60分钟，异种移植小鼠90分钟）。还评估了[(18)F]FE@SUPPY在人和大鼠血浆中的体外稳定性。
[(18)F]FE@SUPPY在富含脂肪的区域摄取高，在脑中摄取低。用MRS1523预处理导致[(18)F]FE@SUPPY摄取减少（p = 0.03），用P-糖蛋白抑制剂tariquidar预处理导致大鼠脑中[(18)F]FE@SUPPY摄取增加1.24倍（p = 0.09）。各治疗组血浆和脑中代谢物无显著差异。然而，阻断后[(18)F]FE@SUPPY的血浆浓度降至与大鼠脑内相似的水平。与[(18)F]FDG摄取情况相反（p = 0.12），异种移植模型显示表达人A3R的CHO细胞的组织块中[(18)F]FE@SUPPY摄取显著增加（p = 0.03）。[(18)F]FE@SUPPY在人血浆中稳定。
在注射了表达人A3R细胞的异种移植小鼠中发现[(18)F]FE@SUPPY有选择性且显著的示踪剂摄取。这一发现支持在“人源化动物模型”中评估[(18)F]FE@SUPPY的策略。总之，临床前评估表明[(18)F]FE@SUPPY适合作为人体A3R PET示踪剂。
