Glioblastoma (GBM) is the most common primary brain tumor in adults and a deadly disease with a median life expectancy of approximately fourteen months. The imaging and treatment of GBM and other gliomas is complicated by tumor regions with an intact blood-brain barrier (BBB) and difficulty in distinguishing treatment effects from viable tumor. Many conventional contrast agents including gadolinium chelates for magnetic resonance imaging (MRI) and positron emission tomography (PET) tracers do not cross the BBB and, therefore, cannot visualize the entire tumor. A leading class of PET agents, radiolabeled amino acids (AAs) targeting system L amino acid transport, can cross the BBB. However, system L substrates have limitations due to bidirectional transport and washout from some tumors over time. The shortcomings of current neuroimaging techniques result in diagnostic uncertainty, leading to numerous equivocal imaging studies, delays in treatment of recurrences, overtreatment due to false positive imaging results such as radiation necrosis, and in some cases futile therapies. To address the urgent critical need for improved GBM imaging agents, we have developed a novel 18F-labeled amino ester prodrug-based imaging strategy. Our novel 18F-labeled amino ester prodrugs are expected to cross the intact BBB through lipophilic diffusion, undergo cleavage by esterases, and provide higher tumor to brain ratios than system L tracers by concentrating in tumor cells through uptake by AA transporter systems. These properties are expected to lead to higher sensitivity for detecting viable tumor tissue, more accurate definition of tumor boundaries, and better assessment of treatment response than with MRI and currently available PET tracers. This approach will improve the diagnosis, treatment planning, and response assessment in GBM, ultimately leading to improved patient outcomes. In addition, our advance will provide new tools for assessing metabolic pathways involving AAs that do not cross the BBB, such as glutamine. This project will pursued through two Specific Aims:
Specific Aim 1 : Synthesize and characterize the cleavage of 18F-labeled amino ester prodrugs by brain esterases and measure the uptake of the corresponding free amino acids by GBM cells.
Specific Aim 2 : Measure in vivo brain availability and tumor imaging properties of the lead amino ester prodrugs in GBM PDX models.
This research plan focuses on the development and preclinical evaluation of novel 18F-labeled amino ester prodrugs as optimized positron emission tomography (PET) agents for imaging glioblastoma and other brain tumors. A key feature of our novel agents is the use of a cleavable ester that will allow us to image amino acid uptake by glioma cells throughout the tumor volume including regions with relatively intact blood-brain barrier function. These improved PET tracers are expected to better guide the use of both established and experimental therapies, leading to more accurate diagnosis and improved outcomes for neuro-oncology patients.
