Leucine Type Amino Acid Transport In Gliomas

描述（由申请人提供）：本研究项目的目的是利用正电子发射断层扫描（PET）成像技术研究anti- 1-氨基-3-[18F]氟环丁烷-1-羧酸（anti-[F]FACBC）对基于氨基酸运输的胶质瘤的成像。我们的方法将集中于抗[18F]FACBC，这是一种非代谢氨基酸（AA），主要通过“L”大中性AA转运系统（LAT）在肿瘤毛细血管中移动。作为LAT底物的正电子发射器标记的AAs的初步评估显示，它在胶质瘤患者的肿瘤成像中具有良好的潜力。具有最佳成像性能的LAT示踪剂的开发仍然是一个活跃的研究领域。我们选择反[18 f] FACBC作为一个合适的放射性示踪剂成像肿瘤源于我们人类U87神经胶质瘤细胞体外研究证明抗- [18 f] FACBC显示高和选择性吸收LAT和体内研究曾帮工/ - [18 f] FACBC在人类原发性神经胶质瘤(n = 11)和转移性脑瘤(n = 15)显示高6:1肿瘤脑比率支持我们提出的研究来评估反人类[18 f] FACBC为了确定其潜在的作为显像剂神经胶质瘤。本提案的具体目的是：1)在患者治疗过程中，在低级别和高级别胶质瘤中分别进行抗[18F]FACBC和[18F]FDG PET检测抗[18F]FACBC转运率和[18F]FDG代谢：a)肿瘤穿刺活检后；b)放射治疗初始周期后；c) MR成像显示肿瘤进展时；2)在肿瘤活检或切除前进行抗[18F]FACBC和[18F]FDG PET检测抗[18F]FACBC转运率和[18F]FDG代谢，以治疗肿瘤复发或放射性坏死；3)对低、高级别胶质瘤进行抗[18F]FACBC和[18F]FDG PET与MRI共配准，比较肿瘤分布和体积测量结果；4)对MRI非增强肿瘤患者行抗[18F]FACBC和[18F]FDG PET检查，评估抗[18F]FACBC是否比[18F]FDG更准确地区分低级别肿瘤和恶性肿瘤；5)比较肿瘤标本与组织学和anf/-[18F]FACBC成像和动力学的AA转运蛋白特征，以确定LAT表达是否能很好地预测肿瘤控制和生存；6)在患者治疗前进行抗[18F]FACBC扫描，测量低级别胶质瘤中AA转运率：a)肿瘤穿刺活检后；b)在7天内确定测试的再测试变异性。我们的假设是FACBC在神经肿瘤成像应用方面优于FDG。我们期待以下改进：1)在人类中比[18F]FDG更准确的组织学分级；2) LAT在脑肿瘤中的表达上调与肿瘤生长速率、转运速率和肿瘤分级成正比；3)治疗前后肿瘤中抗-[18F]FACBC转运率与生存相关；4)与MRI或[18F]FDG相比，抗[18F]FACBC肿瘤摄取将提供更准确的活肿瘤分布范围的相关性；5)抗[18F]FACBC肿瘤摄取将比MRI和[18F]FDG更准确地区分放射性坏死和活肿瘤。

DESCRIPTION (provided by applicant): The objective of this research project is to investigate anfr-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-[ F]FACBC) to image gliomas based upon amino acid transport with the imaging technique Positron Emission Tomography (PET). Our approach will focus on anti-[18F]FACBC, a non-metabolized amino acid (AA) that moves across tumor capillaries involving primarily the "L" large-neutral AA transport system (LAT). Preliminary evaluation of AAs labeled with positron emitters and which are substrates for the LAT has shown excellent potential for tumor imaging in patients with gliomas. The development of LAT radiotracers with optimal imaging properties remains an active area of investigation. Our choice of anti-[18F]FACBC as a suitable radiotracer for imaging tumors stems from our in vitro studies in human U87 glioma cells demonstrating that anti-[18F]FACBC shows high and selective uptake by the LAT and our in vivo studies with anf/-[18F]FACBC in humans with primary gliomas (n=11) and metastatic brain tumors (n=15) displayed high 6:1 tumor to brain ratios support our proposed studies to evaluate anti-[18F]FACBC in humans in order to determine its potential as an imaging agent for gliomas. The Specific Aims of this proposal are: 1) Perform anti-[18F]FACBC and [18F]FDG PET to measure anti-[18F]FACBC transport rate and [18F]FDG metabolism, respectively in low and high grade gliomas during the course of the patient's treatment: a) After tumor needle biopsy; b) After the initial cycle of radiation therapy; c) When MR imaging indicates tumor progression; 2) Perform anti-[18F]FACBC and [18F]FDG PET to measure anti-[18F]FACBC transport rate and [18F]FDG metabolism just prior to tumor biopsy or resection to address tumor recurrence or radiation necrosis; 3) Perform co-registration of anti-[18F]FACBC and [18F]FDG PET with MRI in low and high grade gliomas to compare measurement of tumor distribution and volume; 4) Perform anti-[18F]FACBC and [18F]FDG PET in patients with MRI nonenhancing tumors to assess whether anti-[18F]FACBC can distinguish low grade tumors from malignant ones more accurately than [18F]FDG; 5) Compare AA transporter character from tumor specimens with histology and anf/-[18F]FACBC imaging and kinetics to determine if LAT expression is a good predictor of tumor control and survival; and 6) Perform anti-[18F]FACBC scans to measure AA transport rate in low grade gliomas prior to the patient's treatment: a) After tumor needle biopsy; and b) at 7 days to determine test re-test variability. Our hypothesis is that FACBC is superior to FDG for neuro tumor imaging applications We expect the following improvements: 1) more accurate histologic grading in humans than [18F]FDG; 2) LAT expression is upregulated in brain tumors in proportion to the growth rate, transport rate and tumor grade; 3) anti-[18F]FACBC transport rate in tumor measured prior to and following therapy will correlate to survival; 4) anti-[18F]FACBC tumor uptake will provide a more accurate correlation of the extent of the viable tumor distribution compared to MRI or with [18F]FDG and 5) anti-[18F]FACBC tumor uptake will provide a more accurate distinction between radiation necrosis and viable tumor than MRI) and [18F]FDG).