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

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. SavonenkoRobert F. Dannals, Mikhail V. Pletnikov, Martin G. Pomper

Research output: Contribution to journalArticlepeer-review

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 non-invasively 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 [ 11 C]CPPC [5-cyano-N-(4-(4-[ 11 C]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. [ 11 C]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 [ 11 C]CPPC to be safe for future human studies. [ 11 C]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.

Original languageEnglish (US)
Pages (from-to)1686-1691
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number5
DOIs
StatePublished - Jan 29 2019

Keywords

  • CSF1R
  • DAM
  • Neuroinflammation
  • Positron-emission tomography
  • [ C]CPPC

ASJC Scopus subject areas

  • General

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