Development of 11CCPPC as a Clinical PET Radioligand Biomarker of Microglial Activation in ALS
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating terminal disease affecting speech and muscle function, with few therapeutic options. Brain inflammation is one of the processes that leads to motor neuron loss in ALS. This brain inflammation comes from cells called microglia. Microglial overactivity and brain inflammation are thought to be important in all forms of ALS and, therefore, what we learn in this study will have broad implications for patients in various stages of the disease. A specific target on microglia called macrophage colony stimulating factor 1 receptor (CSF1R) makes it a promising target for studying microglial activity in ALS. Understanding the location and severity of this brain inflammation can tell us about which patients might be most responsive to therapies directed against brain inflammation in ALS, as well as better understand the disease process. Positron emission tomography (PET) imaging is a technique that uses radioactive molecules attached to a molecule of interest which binds to the desired target, allowing investigators to see the target. The 11CCPPC PET radioligand targets CSF1R in the brain. This radioligand has the potential for providing knowledge about disease diagnosis, prognosis, and whether certain drugs might be beneficial. There are no well-established diagnostic or prognostic imaging modalities for ALS used in clinical practice. The development of this microglial-specific 11CCPPC PET radioligand for imaging patients with ALS has many applications. First, from the standpoint of caring for an ALS patient, a reliable imaging biomarker could improve a doctor s ability to diagnose ALS in a timely manner. This technique could also aid in identifying the vulnerability of certain types of nerve cells in the brain and spinal cord whose function cannot be reliably measured by clinical observation. Because an understanding of ALS prognosis and disease progression over time is so important, this PET radioligand could be a marker that correlates with disease progression allowing doctors, patients, and families to make more informed care decisions. Second, as a predictive biomarker, this PET radioligand could help determine which patients may be most responsive to therapies that target brain inflammation. Given that there are developing studies targeting these cascades, this technology could be used as a pharmacodynamic marker to assess the response to treatment, allowing for more tailored treatment regimens. Third, one of the challenges to the development of new medications for ALS is an understanding, in real time, of how well a drug might be working. For example, in cancer, we know that a drug is working when tumor size shrinks as measured by an image taken by MRI or CT scan. This has allowed for the more rapid development of compounds that are known to have an effect on tumor size. A similar understanding of how well a drug compound can reduce microglial activation in ALS using PET imaging would provide similar therapeutic advances. We anticipate that it will take 2 years to study this imaging technique in ALS patients. At that time, we will have a clear understanding how effective this radioligand is in marking brain inflammation. We will also be able to tell which types of ALS patients might have the most brain inflammation. By performing PET scans in the same ALS patient over the course of their disease, we will also be able to see how the PET signal changes over time and we will be able to compare this with other measures of ALS function including strength, overall ability for carrying out activities of daily living, and other measures of disease that are used in the clinic.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210130
Entities
People
- Nicholas J Maragakis
Organizations
- Johns Hopkins University
- United States Army