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PET Imaging Agents for Protoporphyrin IX

原卟啉 IX PET 成像剂

基本信息

批准号：
10330484
负责人：
Mark Myron Goodman
金额：
$ 21.51万
依托单位：
EMORY UNIVERSITY
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 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10330484
关键词：
3-Dimensional Acids Address Affinity Aminolevulinic Acid Area Benzodiazepine Receptor Biological Markers Brain Brain Neoplasms Breast Calcium Channel Cell Proliferation Cells Cessation of life Chemicals Clinical Clinical Distribution Colon Development Diagnosis Evaluation Excision FDA approved Fluorescence Fluorides Fluorine Glioblastoma Glioma Goals Half-Life Heme Heterogeneity Histopathology Image Image-Guided Surgery In Vitro Infiltration Intracranial Neoplasms Ions Label Ligands Malignant - descriptor Malignant Neoplasms Metabolic Metabolism Methods Mitochondria Modeling Molecular Monitor Neuraxis Operative Surgical Procedures Oral Organ Outer Mitochondrial Membrane Patient-Focused Outcomes Patients Peripheral Porphyrins Positron-Emission Tomography Primary Brain Neoplasms Production Prognosis Prostate Proteins Radiation Radioactivity Radioisotopes Radiolabeled Rattus Rectum Recurrence Resistance development Respiration Rodent Specificity Steroid biosynthesis Testing Time Tissues Tracer Transfection Tumor Subtype Tumorigenicity analog base brain tissue brain tumor imaging cancer type clinical application clinical imaging enantiomer enzyme pathway expression vector fluorodeoxyglucose fluorodeoxyglucose positron emission tomography glioma cell line heme biosynthesis imaging agent imaging approach imaging capabilities imaging modality imaging probe in vivo individualized medicine innovation metabolic imaging molecular imaging neoplastic neoplastic cell non-invasive imaging novel optical imaging pre-clinical protoporphyrin IX radiochemical receptor density receptor expression treatment response tumor tumor behavior tumor progression uptake

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.

项目总结