Leucine Type Amino Acid Transport In Gliomas

描述（由申请方提供）：本研究项目的目的是研究anfr-1-氨基-3-[18 F]氟环丁烷-1-羧酸（抗-[ F]FACBC）通过正电子发射断层扫描（PET）成像技术基于氨基酸转运对胶质瘤进行成像。我们的方法将集中在抗-[18 F]FACBC，一种非代谢氨基酸（AA），主要涉及“L”大中性AA转运系统（LAT）的肿瘤毛细血管移动。用正电子发射体标记的AA作为LAT的底物的初步评价显示出在胶质瘤患者中肿瘤成像的优异潜力。具有最佳成像性能的LAT放射性示踪剂的开发仍然是一个活跃的研究领域。我们选择抗-[18 F]FACBC作为肿瘤成像的合适放射性示踪剂源于我们在人U87胶质瘤细胞中的体外研究，表明抗-[18 F]FACBC显示出LAT的高选择性吸收，并且我们在患有原发性胶质瘤（n=11）和转移性脑肿瘤（n=15）的人体中使用anf/-[18 F]FACBC的体内研究显示高6：1肿瘤与脑的比率支持我们提出的研究，以评估抗-[18 F]FACBC在人类中，以确定其作为神经胶质瘤显像剂的潜力。本建议的具体目的是：1）在患者治疗过程中，分别在低级别和高级别胶质瘤中进行抗[18 F] FACBC和[18 F]FDG PET以测量抗[18 F]FACBC转运率和[18 F]FDG代谢：a）肿瘤穿刺活检后; B）放射治疗的初始周期后; c）当MR成像指示肿瘤进展时; 2）在肿瘤活检或切除之前进行抗-[18 F]FACBC和[18 F]FDG PET以测量抗-[18 F]FACBC转运率和[18 F]FDG代谢，以解决肿瘤复发或放射性坏死; 3）在低级别和高级别胶质瘤中进行抗-[18 F]FACBC和[18 F]FDG PET与MRI的共配准，以比较肿瘤分布和体积的测量; 4）在患有MRI非增强肿瘤的患者中进行抗-[18 F]FACBC和[18 F]FDG PET以评估抗-[18 F]FACBC是否可以比[18 F]FDG更准确地区分低级别肿瘤与恶性肿瘤; 5）将来自肿瘤标本的AA转运体特征与组织学和抗-[18 F]FACBC成像和动力学进行比较以确定LAT表达是否是肿瘤控制和存活的良好预测因子;和6）在患者治疗前进行抗-[18 F]FACBC扫描以测量低级别神经胶质瘤中的AA转运率：a）在肿瘤穿刺活检后;和B）在第7天以确定测试再测试变异性。我们的假设是FACBC在神经肿瘤成像应用中上级FDG。我们预期以下改进：1）在人类中比[18 F]FDG更准确的组织学分级; 2）在脑肿瘤中LAT表达与生长速率、转运速率和肿瘤分级成比例地上调; 3）在治疗之前和之后测量的肿瘤中的抗-[18 F]FACBC转运速率将与存活相关; 4）与MRI或[18 F]FDG相比，抗[18 F]FACBC肿瘤摄取将提供存活肿瘤分布程度的更准确相关性，5）与MRI和[18 F] FDG相比，抗[18 F]FACBC肿瘤摄取将提供放射性坏死和存活肿瘤之间更准确的区分。

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).