Sensitive and specific tools to diagnose and monitor diseases are crucial. In the first part of this application (K99), I describe my current postdoctorl project to develop a PET tracer for multiple sclerosis (MS); a common neurological condition that affects young adults. This tracer binds to axonal voltage gated K+ channels that have been exploited for therapy but never for imaging. Unlike the tracers for myelin developed to date, this tracer has low baseline uptake in white matter that increases upon demyelination, making it a very promising tool to monitor changes in myelination. Such a tool could improve how MS is monitored and diagnosed and provide the necessary endpoints to evaluate new therapies that promote remyelination. Using the principles and expertise acquired on this project, I propose to develop a new tool for imaging monoclonal antibodies (mAbs) using PET that does not involve radioactive antibodies (R00). This will be accomplished by adding to the antibody a short peptide that is designed to recognize a small molecule tracer. Because small molecules have much faster pharmacodynamics than antibodies this offers the possibility of using short-lived isotopes like F-18 and low doses of radiation. In the dawn of the therapeutic monoclonal antibody era a general tool to visualize and predict response to mAb therapies has the potential to improve patient care and decrease costs associated with these therapies.
There are many therapeutic drugs with extraordinary affinity and specificity. Herein, I propose two novel imaging approaches based on turning effective therapeutics into imaging markers. Specifically, a tracer for multiple sclerosis based on 4-aminopyridine and a general approach to image monoclonal antibodies.
| Basuli, Falguni; Zhang, Xiang; Brugarolas, Pedro et al. (2018) An efficient new method for the synthesis of 3-[18 F]fluoro-4-aminopyridine via Yamada-Curtius rearrangement. J Labelled Comp Radiopharm 61:112-117 |
| Brugarolas, Pedro; Sánchez-RodrÃguez, Jorge E; Tsai, Hsiu-Ming et al. (2018) Development of a PET radioligand for potassium channels to image CNS demyelination. Sci Rep 8:607 |
