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A radioligand for in vitro autoradiography of CSF1R in post-mortem CNS tissues.
Foss, Catherine A; Naik, Ravi; Das, Deepankar; Cha, Hyojin; Minn, Il; Hall, Andrew; Finley, Paige; Wu, Sophia Jiang; Du, Yong; Dannals, Robert F; Pomper, Martin G; Horti, Andrew G.
Affiliation
  • Foss CA; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 1550 Orleans St. CRB2 493, Baltimore, MD, 21228, USA. cfoss1@jhmi.edu.
  • Naik R; Department of Pediatrics, Center for Infection and Inflammation Imaging Research, Johns Hopkins University, Baltimore, MD, USA. cfoss1@jhmi.edu.
  • Das D; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 1550 Orleans St. CRB2 493, Baltimore, MD, 21228, USA.
  • Cha H; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 1550 Orleans St. CRB2 493, Baltimore, MD, 21228, USA.
  • Minn I; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 1550 Orleans St. CRB2 493, Baltimore, MD, 21228, USA.
  • Hall A; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 1550 Orleans St. CRB2 493, Baltimore, MD, 21228, USA.
  • Finley P; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 1550 Orleans St. CRB2 493, Baltimore, MD, 21228, USA.
  • Wu SJ; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 1550 Orleans St. CRB2 493, Baltimore, MD, 21228, USA.
  • Du Y; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 1550 Orleans St. CRB2 493, Baltimore, MD, 21228, USA.
  • Dannals RF; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 1550 Orleans St. CRB2 493, Baltimore, MD, 21228, USA.
  • Pomper MG; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 1550 Orleans St. CRB2 493, Baltimore, MD, 21228, USA.
  • Horti AG; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 1550 Orleans St. CRB2 493, Baltimore, MD, 21228, USA.
EJNMMI Res ; 14(1): 76, 2024 Aug 26.
Article in En | MEDLINE | ID: mdl-39186197
ABSTRACT

BACKGROUND:

Reactive microglia and recruited peripheral macrophages contribute to the pathogenesis of Alzheimer's dementia (AD). Monocytes, macrophages and microglia all express the marker colony-stimulating factor 1 receptor (CSF1R). 4-Cyano-N-(4-(4-methylpiperazin-1-yl)-2-(4-methylpiperidin-1-yl)phenyl)-1H-pyrrole-2-carboxamide (1) is a high-affinity antagonist for CSF1R. We report the radiosynthesis of both [3H]1 and [11C]1. The PET imaging properties of [11C]1 in mice and baboon were investigated. [3H]1 was studied in Bmax measurement in post-mortem autoradiography in the frontal cortex, inferior parietal cortex and hippocampus from donors diagnosed with AD and age-matched controls. In vitro binding affinity of 1 was measured commercially. Nor-methyl-1 precursor was radiolabeled with [11C]iodomethane or [3H]iodomethane to produce [11C]1 and [3H]1, respectively. Ex vivo brain biodistribution of [11C]1 was compared in normal mice versus lipopolysaccharide-administered (LPS) murine model of neuroinflammation. Dynamic PET imaging was performed in a healthy male Papio anubis baboon. Post-mortem autoradiography with [3H]1 was performed in frozen sections using a standard saturation binding technique.

RESULTS:

Compound 1 exhibits a high in vitro CSF1R binding affinity (0.59 nM). [11C]1 was synthesized with high yield. [3H]1 was synthesized similarly (commercially). Biodistribution of [11C]1 in healthy mice demonstrated moderate brain uptake. In LPS-treated mice the brain uptake of [11C]1 was ~ 50% specific for CSF1R. PET/CT [11C]1 study in baboon revealed low brain uptake (0.36 SUV) of [11C]1. Autoradiography with [3H]1 gave significantly elevated Bmax values in AD frontal cortex versus control (47.78 ± 26.80 fmol/mg vs. 12.80 ± 5.30 fmol/mg, respectively, P = 0.023) and elevated, but not significantly different binding in AD hippocampus grey matter and inferior parietal cortex (IPC) white matter.

CONCLUSIONS:

Compound 1 exhibits a high in vitro CSF1R binding affinity. [11C]1 specifically labels CSF1R in the mouse neuroinflammation, but lacks the ability to efficiently cross the blood-brain barrier in baboon PET. [3H]1 specifically labels CSF1R in post-mortem human brain. The binding of [3H]1 is significantly higher in the post-mortem frontal cortex of AD versus control subjects.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: EJNMMI Res Year: 2024 Document type: Article Affiliation country:
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: EJNMMI Res Year: 2024 Document type: Article Affiliation country: