PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R).

Abstract

While neuroinflammation is an evolving concept and the cells involved and their functions are being defined, microglia are understood to be a key cellular mediator of brain injury and repair. The ability to measure microglial activity specifically and noninvasively would be a boon to the study of neuroinflammation, which is involved in a wide variety of neuropsychiatric disorders including traumatic brain injury, demyelinating disease, Alzheimer's disease (AD), and Parkinson's disease, among others. We have developed [11C]CPPC [5-cyano-N-(4-(4-[11C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide], a positron-emitting, high-affinity ligand that is specific for the macrophage colony-stimulating factor 1 receptor (CSF1R), the expression of which is essentially restricted to microglia within brain. [11C]CPPC demonstrates high and specific brain uptake in a murine and nonhuman primate lipopolysaccharide model of neuroinflammation. It also shows specific and elevated uptake in a murine model of AD, experimental allergic encephalomyelitis murine model of demyelination and in postmortem brain tissue of patients with AD. Radiation dosimetry in mice indicated [11C]CPPC to be safe for future human studies. [11C]CPPC can be synthesized in sufficient radiochemical yield, purity, and specific radioactivity and possesses binding specificity in relevant models that indicate potential for human PET imaging of CSF1R and the microglial component of neuroinflammation.

• Authors: Andrew G Horti, Ravi Naik, Catherine A Foss, Il Minn, Varia Misheneva, Yong Du, Yuchuan Wang, William B Mathews, Yunkou Wu, Andrew Hall, Catherine LaCourse, Hye-Hyun Ahn, Hwanhee Nam, Wojciech G Lesniak, Heather Valentine, Olga Pletnikova, Juan C Troncoso, Matthew D Smith, Peter A Calabresi, Alena V Savonenko, Robert F Dannals, Mikhail V Pletnikov, Martin G Pomper
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 5 Pg. 1686-1691 (01 29 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 30635412 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CSF1R protein, human
• Radiopharmaceuticals
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
• Macrophage Colony-Stimulating Factor

Topics

• Alzheimer Disease (metabolism)
• Animals
• Brain (metabolism)
• Disease Models, Animal
• Inflammation (metabolism)
• Macrophage Colony-Stimulating Factor (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (metabolism)
• Plaque, Amyloid (metabolism)
• Positron-Emission Tomography (methods)
• Primates
• Radiopharmaceuticals (metabolism)
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)