PDF(Pubmed)
Abstract：
O-([18F]Fluoroethyl)-l-tyrosine ([18F]FET) is actively transported into the brain and cancer cells by LAT1 and possibly other amino acid transporters, which enables brain tumor imaging by positron emission tomography (PET). However, tumor delivery of this probe in the presence of competing amino acids may be limited by a relatively low affinity for LAT1. The aim of the present work was to evaluate the meta-substituted [18F]FET analog m-[18F]FET and the methyl ester [18F]FET-OMe, which were designed to improve tumor delivery by altering the physicochemical, pharmacokinetic, and/or transport properties. Both tracers could be prepared with good radiochemical yields of 41-56% within 66-90 min. Preclinical evaluation with [18F]FET as a reference tracer demonstrated reduced in vitro uptake of [18F]FET-OMe by U87 glioblastoma cells and no advantage for in vivo tumor imaging. In contrast, m-[18F]FET showed significantly improved in vitro uptake and accelerated in vivo tumor accumulation in an orthotopic glioblastoma model. As such, our work identifies m-[18F]FET as a promising alternative to [18F]FET for brain tumor imaging that deserves further evaluation with regard to its transport properties and in vivo biodistribution.
摘要：
O-（[18F]氟乙基）-1-酪氨酸（[18F]FET）通过LAT1和可能的其他氨基酸转运蛋白被主动转运到大脑和癌细胞中。通过正电子发射断层扫描（PET）实现脑肿瘤成像。然而,在存在竞争性氨基酸的情况下,该探针的肿瘤递送可能受到对LAT1的相对低亲和力的限制。本工作的目的是评估元取代的[18F]FET模拟m-[18F]FET和甲酯[18F]FET-OMe，它们旨在通过改变物理化学来改善肿瘤的输送，药代动力学，和/或运输属性。两种示踪剂均可在66-90分钟内以41-56％的良好放射化学产率制备。以[18F]FET作为参考示踪剂的临床前评估表明，U87胶质母细胞瘤细胞对[18F]FET-OMe的体外摄取减少，对体内肿瘤成像没有优势。相比之下,m-[18F]FET在原位成胶质细胞瘤模型中显示出显著改善的体外摄取和加速的体内肿瘤积累。因此，我们的工作确定m-[18F]FET是[18F]FET的有希望的替代脑肿瘤成像，值得就其运输特性和体内生物分布进行进一步评估。
