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

Andrew Horti, Ravi Naik, Catherine Foss, Il Minn, Varia Misheneva, Yong Du, Yuchuan Wang, William B Mathews, Yunkou Wu, Andrew Hall, Catherine LaCourse, Hye Hyun Ahn, Hwanhee Nam, Wojciech Lesniak, Heather Valentine, Olga Pletnikova, Juan C Troncoso, Matthew D. Smith, Peter Calabresi, Alena SavonenkoRobert F Dannals, Mikhail Pletnikov, Martin Gilbert Pomper

Research output: Contribution to journalArticle

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 [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.

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

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Macrophage Colony-Stimulating Factor Receptors
Macrophage Colony-Stimulating Factor
Microglia
Alzheimer Disease
Demyelinating Diseases
Brain
Colony-Stimulating Factor Receptors
Radiometry
Aptitude
Autoimmune Experimental Encephalomyelitis
Brain Injuries
Radioactivity
Primates
Parkinson Disease
Lipopolysaccharides
Electrons
Ligands

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

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title = "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 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 [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.",
keywords = "CSF1R, DAM, Neuroinflammation, Positron-emission tomography, [C]CPPC",
author = "Andrew Horti and Ravi Naik and Catherine Foss and Il Minn and Varia Misheneva and Yong Du and Yuchuan Wang and Mathews, {William B} and Yunkou Wu and Andrew Hall and Catherine LaCourse and Ahn, {Hye Hyun} and Hwanhee Nam and Wojciech Lesniak and Heather Valentine and Olga Pletnikova and Troncoso, {Juan C} and Smith, {Matthew D.} and Peter Calabresi and Alena Savonenko and Dannals, {Robert F} and Mikhail Pletnikov and Pomper, {Martin Gilbert}",
year = "2019",
month = "1",
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doi = "10.1073/pnas.1812155116",
language = "English (US)",
volume = "116",
pages = "1686--1691",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
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TY - JOUR

T1 - PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R)

AU - Horti, Andrew

AU - Naik, Ravi

AU - Foss, Catherine

AU - Minn, Il

AU - Misheneva, Varia

AU - Du, Yong

AU - Wang, Yuchuan

AU - Mathews, William B

AU - Wu, Yunkou

AU - Hall, Andrew

AU - LaCourse, Catherine

AU - Ahn, Hye Hyun

AU - Nam, Hwanhee

AU - Lesniak, Wojciech

AU - Valentine, Heather

AU - Pletnikova, Olga

AU - Troncoso, Juan C

AU - Smith, Matthew D.

AU - Calabresi, Peter

AU - Savonenko, Alena

AU - Dannals, Robert F

AU - Pletnikov, Mikhail

AU - Pomper, Martin Gilbert

PY - 2019/1/29

Y1 - 2019/1/29

N2 - 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 [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.

AB - 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 [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.

KW - CSF1R

KW - DAM

KW - Neuroinflammation

KW - Positron-emission tomography

KW - [C]CPPC

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DO - 10.1073/pnas.1812155116

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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