1) Tumor imaging with cationic amino acid transport substrates:

Cationic amino acid transport is a promising but relatively unexplored target for tumor imaging. We have developed a lead 1H-[1,2,3]triazole substitutued amino acid, (S)-[F-18]AFETP, that is prepared through the click reaction. This tracer has demonstrated promising imaging tumor imaging properties in the rat 9L gliosarcoma, the mouse DBT glioma models of glioblastoma, sarcoma, and in the human-in-mouse (HIM) model of breast cancer. We are currently preparing a series of analogues of [F-18]AFETP to optimize selectivity for cationic amino acid transport and testing these agents in a rodent model of  radiation therapy.

Figure 1. MicroPET and MRI images acquired in a mouse with an intracranial DBT tumor. Bioluminesence imaging of luciferase expression by DBT tumor cells can be used to monitor tumor viability prior to microPET and MR imaging.

Figure 2. MicroPET images in a mouse with a human-derived breast cancer implanted in a humanized mammary fat pad (red circle).

2) F-18 labeled amino acids targeting system A, system L, and cationic amino acid transport to distinguish viable tumor from radiation necrosis:

Therapy for primary and metastatic brain tumors often involves radiation therapy, but MRI and FDG-PET frequently cannot distinguish viable tumor from radiation effects including radiation necrosis. We are utilizing amino acids that target different transport systems in a mouse model of radiation therapy to determine which class of radiolabeled amino acids is best-suited for this application. Tracers that we are evaluating in this model include [F-18]FET for system L, (R)-[F-18]MeFAMP for system A, and (S)-[F-18]AFETP for cationic amino acid transport systems.

Figure 3. The system A transport substrate, MeFAMP, is retained in DBT tumors (top row, red circle), but washes out of radiation necrosis (bottow row, yellow circle) over the course of a 4 hour small animal PET study. MR images are shown on the right to demonstrate the anatomic correlates.

3) FDOPA-PET/MRI to monitor response to anti-angiogenic therapy with bevacizumab:

MRI is the an effective imaging modality for brain tumors, but it has substantial limitations for visualizing non-enhancing regions, distinguishing viable tumor from treatment effects, and monitoring response to chemotherapies. In collaboration with Drs. Josh Rubin and Karen Gauvain, we are testing the effectiveness of the system L amino acid, [F-18]FDOPA, to detect response to bevacizumab, an anti-angiogenic therapy, early in the course of therapy in pediatric neuro-oncology patients.

Figure 4.  A recurrent brainstem pilocytic astrocytoma in a pediatric patient shows high uptake of FDOPA at baseline which decreases in size after 4 weeks of bevacizumab (upper row).  T1 post-contrast  (middle row) and FLAIR (lower row) MR images demonstrate decreased enhancement with bevacizumab therapy but no substantial change in size. The FDOPA-PET and MR images were acquired simultaneously using the Siemens mMR PET/MRI system.

4) Molecular imaging of Alzheimer's disease and other neurodegenerative diseases:

The development of PET tracers that can detect and quantify amyloid and tau, two key protein markers of the pathology underlying Alzheimer's disease, in the brain of living humans provide new tools for the diagnosis of Alzheimer's disease and are assisting in the development of new treatments for this devastating disease. Led by the Knight Alzheimer's Disease Research Center (ADRC) at Washington University, we are conducting imaging studies to understand the time course and the cognitive correlates of amyloid and tau PET imaging studies in Alzheimer's and other neurodegenerative disease.

Figure 5. Tau-PET and amyloid-PET in a person with a clinical diagnosis of Alzheimer's disease (A) and in a person with no cognitive deficits (B). Abnormal tau is seen on PET in subject A in the temporal lobes (A) based on higher tracer uptake ([F-18]T807) as shown by red arrows. Abnormal amyloid is also seen in subject A based on higher tracer uptake ([F-18]florbetapir) throughout the cerebral cortex leading to loss of gray-white contrast). These imaging findings confirm the presence of the two key proteins used to diagnosis Alzheimer's disease. Subject B has no focal tau deposition or increased cortical amyloid deposition based on PET imaging.