I recently attended the 49th annual Drug Information Association (DIA) conference in Boston and had the good fortune to attend individual sessions as well as explore the exhibition hall. With an interest in medical imaging and an eye for hot topics, I spotted a session entitled “Molecular Imaging: Utilizing it as an Effective Drug Development Tool.” This session, featuring three speakers, focused on the uses of molecular imaging agents in both preclinical and clinical settings.
In this post, I will share highlights from a presentation given by Dr. Jonathan McConathy, an Assistant professor of Radiology at Washington University. In addition to discussing various types of molecular tracers and imaging modalities, Dr. McConathy provided a nice overview of the workflow for the development of small molecule radioactive tracers used for imaging.
The development of a small molecule tracer starts with a lead compound, obtained from the scientific or patent literature, drug libraries, or existing experimental data. The lead compound is then synthesized and labeled with radioactivity to enable detection. Once labeled, the tracer typically undergoes a panel of in vitro assays, including target binding assays (to measure affinity), competition assays (to measure specificity), and uptake assays (to measure transport into cells). Once sufficient biochemical data is obtained, the tracer can advance to preclinical studies, being put to the test in bio-distribution assays and other small animal imaging studies with the goal of getting to human studies for validation.
What I found fascinating about Dr McConathy's talk was the way he brought this workflow to life by discussing the development of amyloid plaque tracers, an area of keen interest by those in the Alzheimer's Disease (AD) field. Amyloid PET is a hot topic in nuclear medicine and Alzheimer's research. Tracer development in this field is especially challenging since compounds requires access to the brain (must be able to traverse the blood brain barrier) and validation requires brain histopathology at autopsy.
Amyloid Plaques and Alzheimer's Disease
Amyloid plaques are the hallmark of Alzheimer's Disease (AD) and their presence are required for the Alzheimer's diagnosis. Thioflavin T (ThioT) and related compounds have been used for many years to stain and visualize amyloid plaques. Two scientists at the University of Pittsburgh, Chester Mathis and William Klunk, derivitized and radiolabeled ThioT to create a compound called C11-PiB, which gains access to the brain (achieved by removing a charge) and could be detected using PET (due to the C11 radiolabel).
This compound formed the molecular foundation for newer derivatives including Florbetapir (Eli Lilly/Avid) and Flutemetamol (GE) which are labled with Flourine-18, a longer lasting radioisotope with improved manufacturing. Binding studies with these types of compounds show high affinity for amyloid plaques, uptake in the cortex of AD patients (the site of amyloid plaques) and co-localize with ThioT dyes, demonstrating that they bind there target very well and with high specificity. Additional studies in non-human primates helped to select lead compounds for translation studies in humans.
Imaging Tracer Conclusions
Dr. McConathy concluded his talk by showing results from a Phase III AD clinical trial which showed a positive correlation between the binding of Florbetapir in the brains of AD patients and the presence of amyloid plaques by histopathology (1). He also presented data from a Phase II clinical trial of an experimental MAb (bapineuzumab) for AD therapy (2). This study used the compound C11-PiB as a proxy for amyloid plaques to monitor the efficacy of antibody treatment. In these types of studies, molecular tracers like Florbetapir and C11-PiB inform treatment efficacy and the design of future clinical trials.
There is still much work to be done to develop and validate molecular tracers with desired biochemical properties to be used as endpoints in clinical trials. The tremendous amount of work that goes into their development and validation with the goal of FDA approval is a testimony to their importance in modern day medicine.
References
- Clark CM et al., 2011. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 305:275-83
- Rinne JO et al., 2010. 11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. The Lancet Neurology 9:363-372
