The impetus for this proposal is the increasing need for sophisticated human molecular imaging tools to advance human health. Drivers that are creating this unmet need are the evolution in the pathogenesis of various human diseases (e.g., atherosclerosis, various cancers and Alzheimer's Disease) that limit the applicability of pre-clinical disease models, the desire for noninvasive readouts in humans to facilitate drug discovery and development and for the successful implementation of the ongoing efforts to make precision medicine a reality. Although PET radiotracers are particularly attractive in this regard, there are several obstacles to the successful translation of new PET radiotracers from the bench to the clinic. Examples range from the low level of commercial investment to major development bottle-necks including the need for simplified synthetic schemes to facilitate dissemination, limited availability at a single-site of diverse pre-clinical models of disease necessary for radiotracer evaluation, the capability to perform first-in-man evaluation of new radiotracers is limited to a few centers nationwide and the lack of available training opportunities at emerging imaging programs, particularly those with less expertise in synthetic and radiochemistry. We are proposing establishing the PET Radiotracer Translation and Resource Center (PET-RTRC) by leveraging the expertise at Washington University (WU) and the Mallinckrodt Institute of Radiology (MIR) in PET radiotracer design, development, training and use with that of research groups throughout the country who are studying molecular and cellular processes of interest to facilitate the development and dissemination of novel PET radiotracers. Our vision is to expand the PET radiotracer program here at WU and MIR to a national scale. To realize this vision we will address the following Specific Aims:
Aim 1 : The Technological Research & Development (TR&D) Projects will develop a portfolio of PET radiotracers for human imaging to detect important molecular and cellular events that modulate the ubiquitous disease processes of inflammation (sphingosine-1-phosphate receptor 1 and various chemokines) and oxidative stress (inducible form of nitric oxide synthase and total reactive oxygen/nitrogen species).
Aim 2 : Create a distributed model for pre-clinical evaluation to both shorten the radiotracer development timeline and importantly expand the translational potential of novel PET radiotracers to enhance research nationwide by engaging Collaborative Projects (CPs) from both within and outside WU to evaluate radiotracers developed by TR&Ds. Numerous strategies to optimize the ?push-pull? interaction between the Center and CPs are proposed.
Aim 3 : Facilitate first-in-man studies by providing the infrastructure (e.g., GMP capabilities) and expertise (e.g, toxicity and dosimetry evaluation; Chemistry, Manufacturing and Control procedures; and eIND submission and maintenance) necessary for initial human evaluation and subsequent dissemination.
Aim 4 : Establishing a Training and Dissemination Core that will: A) Provide a resource for training of individuals in PET radiotracer synthesis and scientists who use this technology as well as in the detailed steps taken to complete the regulatory requirements for human use of the radiotracers produced by the Center and; B) Provide a resource to increase the use and awareness of the radiotracers developed by the PET-RTRC such as identification of Service Projects that will utilize the most promising radiotracers developed by the TR&Ds, and development and maintenance of a website describing PET-RTRC activities. The Administrative Core will oversee PET-RTRC operations under the guidance of the Executive Committee and establish key functionalities, such as the Tracer Review Committee and Quantitative Imaging/Informatics Resource, and the External Advisory Committee to ensure efficient operation of this BRTC so that it meets its scientific, training and dissemination objectives.
The PET Radiotracer Translation and Resource Center (PET-RTRC) will collaborate with research groups throughout the country who are studying inflammation and oxidative stress in common diseases such as atherosclerosis, various cancers, Multiple Sclerosis, and Alzheimer's disease, to facilitate the development and dissemination of novel PET radiotracers to study these processes. The objective of the Center is to provide these radiotracers and others currently available to interested collaborators around the country with the goal of using them in biomedical research to improve human health.
