PROJECT SUMMARY/ABSTRACT
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.