PET Imaging Agents for Protoporphyrin IX
原卟啉 IX PET 成像剂
基本信息
- 批准号:10199473
- 负责人:
- 金额:$ 18.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcidsAddressAffinityAminolevulinic AcidAreaBenzodiazepine ReceptorBiological MarkersBrainBrain NeoplasmsBreastCalcium ChannelCell ProliferationCellsCessation of lifeChemicalsClinicalClinical DistributionColonDevelopmentDiagnosisEvaluationExcisionFDA approvedFluorescenceFluoridesFluorineGlioblastomaGliomaGoalsHalf-LifeHemeHeterogeneityHistopathologyImageImage-Guided SurgeryIn VitroInfiltrationIntracranial NeoplasmsIonsLabelLigandsMalignant - descriptorMalignant NeoplasmsMetabolicMetabolismMethodsMitochondriaModelingMolecularMonitorNeuraxisOperative Surgical ProceduresOralOrganOuter Mitochondrial MembranePatient-Focused OutcomesPatientsPeripheralPorphyrinsPositron-Emission TomographyPrimary Brain NeoplasmsProductionPrognosisProstateProteinsRadiationRadioactivityRadioisotopesRadiolabeledRattusRectumRecurrenceResistance developmentRespirationRodentSpecificitySteroid biosynthesisTestingTimeTissuesTracerTransfectionTumor SubtypeTumorigenicityanalogbasebrain tissuebrain tumor imagingcancer typeclinical applicationclinical imagingenantiomerenzyme pathwayexpression vectorfluorodeoxyglucosefluorodeoxyglucose positron emission tomographyglioma cell lineheme biosynthesisimaging agentimaging approachimaging capabilitiesimaging modalityimaging probein vivoindividualized medicineinnovationmetabolic imagingmolecular imagingneoplasticneoplastic cellnon-invasive imagingnoveloptical imagingpre-clinicalprotoporphyrin IXradiochemicalreceptor densityreceptor expressiontreatment responsetumortumor behaviortumor progressionuptake
项目摘要
Project Summary
Primary brain tumor is a major central nervous system malignancy with 23,800 estimated total new
cases in the US in 2017 resulting in 16,700 deaths. High grade glioblastomas (HGG; WHO grades III and IV) in
particular carry a dismal prognosis. Glioblastomas are known for their molecular and cellular heterogeneity
which contributes to the highly aggressive malignant behaviors of tumor cells, including high proliferation,
infiltration and development of resistance to treatment. Therefore, non-invasive imaging approaches that can
provide molecular and metabolic information of the glioblastomas are important to characterize a specific tumor
for subtype specific and individualized treatments. As a non-invasive clinical imaging modality, positron
emission tomography (PET) is capable of molecular and metabolic imaging applications, however, its
application in brain tumor is limited. The clinical standard of fluorodeoxyglucose (FDG) PET has low specificity
and is not appropriate for brain tumor imaging given the high FDG uptake in normal brain tissue. Currently,
there is a significant unmet need in molecular imaging probes for imaging highly heterogeneous and infiltrating
gliomas. The overall objective of this exploratory project is to develop a fluorine-18 labeled analog of 5-
aminolevulinic acid (5-ALA), which is an FDA approved imaging tracer for intraoperative imaging of gliomas, to
provide molecular and metabolic information of the glioma. This innovative new PET imaging capability can be
used to characterize a tumor for subtype specific diagnosis and clinical decisions on individualized treatments
as well as monitoring the treatment responses. The central hypothesis of this proposal is that a fluorine-18
labeled 5-ALA will enable PET imaging for glioma metabolism and activity on tumorigenicity and cellular
proliferation based upon tumor cell metabolizing 5-ALA to produce protoporphyrin IX in highly heterogeneous
and infiltrating gliomas. This hypothesis and scientific premise of the project are supported by our preliminary
findings that: 1) in vivo pre-clinical PET evaluation of 13N-5-ALA with rats bearing intracranial 9L gliomas
demonstrated highly selective uptake of 13N-5-ALA within the tumor, and tumor specific contrast without
background; 2) racemic 3-fluoro-5-ALA shows greater substrate reactivity for protoporphyrin IX synthesis in
glioma cells than 5-ALA. Thus, our exploratory development of this novel PET tracer for brain tumor imaging
will focus on the following specific aims: 1. to synthesize and in vitro characterize R- and S-3-fluoro-5-ALA; 2.
to develop radiolabeling methods for the candidate R- and S-3-[18F] fluoro-5-ALA ligands; and 3. to determine
whether developed R- and S-3-[18F] fluoro-5-ALA ligand candidates can be selectively taken up in the
intracranial tumors in rodent orthotopic models of glioblastomas.
项目摘要
原发性脑肿瘤是一种主要的中枢神经系统恶性肿瘤,
2017年,美国的病例导致16,700人死亡。高级别胶质母细胞瘤(HGG; WHO III级和IV级)
尤其是预后惨淡。胶质母细胞瘤以其分子和细胞异质性而闻名
其导致肿瘤细胞的高度侵袭性恶性行为,包括高度增殖,
渗透和对处理的抗性的发展。因此,非侵入性成像方法,
提供胶质母细胞瘤的分子和代谢信息对于表征特定肿瘤是重要的
用于亚型特异性和个体化治疗。作为一种非侵入性的临床成像方式,正电子
发射断层扫描(PET)能够用于分子和代谢成像应用,然而,其
在脑肿瘤中的应用受到限制。FDG PET的临床标准特异性较低
并且由于正常脑组织中的高FDG摄取而不适于脑肿瘤成像。目前,
对用于成像高度异质性和浸润性的分子成像探针存在显著的未满足的需求
神经胶质瘤该探索性项目的总体目标是开发一种氟-18标记的5-氨基-1,2-二氢吲哚类似物。
氨基乙酰丙酸(5-ALA)是FDA批准的用于神经胶质瘤术中成像的成像示踪剂,
提供胶质瘤的分子和代谢信息。这种创新的PET成像能力可以
用于表征肿瘤的亚型特异性诊断和个体化治疗的临床决策
以及监测治疗反应。这一提议的核心假设是,
标记的5-ALA将使胶质瘤代谢和致瘤性和细胞活性的PET成像成为可能。
基于肿瘤细胞代谢5-ALA以产生原卟啉IX的增殖,
和浸润性神经胶质瘤我们的初步研究结果支持了这一假设和科学前提。
发现:1)13 N-5-ALA与颅内9 L胶质瘤大鼠的体内临床前PET评价
证实了肿瘤内13 N-5-ALA的高度选择性摄取,并且肿瘤特异性造影剂没有
背景; 2)外消旋3-氟-5-ALA显示出对原卟啉IX合成的更大的底物反应性,
胶质瘤细胞比5-ALA。因此,我们探索性地开发这种新型PET示踪剂用于脑肿瘤成像,
将着重于以下具体目标:1.合成并体外表征R-和S-3-氟-5-ALA; 2.
开发候选R-和S-3-[18 F]氟-5-ALA配体的放射性标记方法;以及3.以确定
开发的R-和S-3-[18F]氟-5-ALA配体候选物是否可以选择性地被吸收在
在啮齿动物胶质母细胞瘤原位模型中的颅内肿瘤。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mark Myron Goodman其他文献
Mark Myron Goodman的其他文献
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{{ truncateString('Mark Myron Goodman', 18)}}的其他基金
Imaging Bacterial Infections in Vivo: First in Man Studies
体内细菌感染成像:人类研究中的首次
- 批准号:
10543621 - 财政年份:2021
- 资助金额:
$ 18.26万 - 项目类别:
Imaging Bacterial Infections in Vivo: First in Man Studies
体内细菌感染成像:人类研究中的首次
- 批准号:
10611527 - 财政年份:2021
- 资助金额:
$ 18.26万 - 项目类别:
Imaging Bacterial Infections in Vivo: First in Man Studies
体内细菌感染成像:人类研究中的首次
- 批准号:
10155704 - 财政年份:2021
- 资助金额:
$ 18.26万 - 项目类别:
Imaging bacterial infections with 2nd generation maltodextrins
使用第二代麦芽糊精对细菌感染进行成像
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- 资助金额:
$ 18.26万 - 项目类别:
Imaging bacterial infections with 2nd generation maltodextrins
使用第二代麦芽糊精对细菌感染进行成像
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10417147 - 财政年份:2020
- 资助金额:
$ 18.26万 - 项目类别:
Imaging bacterial infections with 2nd generation maltodextrins
使用第二代麦芽糊精对细菌感染进行成像
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10673086 - 财政年份:2020
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$ 18.26万 - 项目类别:
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18F 共轭麦芽糖糊精用于检测医疗器械感染
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9056161 - 财政年份:2015
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$ 18.26万 - 项目类别:
18F Conjugated Maltodextrins for the Detection of Medical Device Infections
18F 共轭麦芽糖糊精用于检测医疗器械感染
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9137678 - 财政年份:2015
- 资助金额:
$ 18.26万 - 项目类别:
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