Discovery of a CSF-1R inhibitor and PET tracer for imaging of microglia and macrophages in the brain.

Autor: van der Wildt B; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, School of Medicine, Stanford, CA, USA., Klockow JL; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, School of Medicine, Stanford, CA, USA., Miao Z; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, School of Medicine, Stanford, CA, USA., Reyes ST; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, School of Medicine, Stanford, CA, USA., Park JH; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, School of Medicine, Stanford, CA, USA., Shen B; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, School of Medicine, Stanford, CA, USA., Chin FT; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, School of Medicine, Stanford, CA, USA. Electronic address: chinf@stanford.edu.
Jazyk: angličtina
Zdroj: Nuclear medicine and biology [Nucl Med Biol] 2022 Nov-Dec; Vol. 114-115, pp. 99-107. Date of Electronic Publication: 2022 Nov 04.
DOI: 10.1016/j.nucmedbio.2022.10.003
Abstrakt: Colony stimulating factor 1 receptor (CSF-1R) is a kinase expressed on macrophages and microglia in the brain. It has been recognized as a potential drug and imaging target in treatment of neuroinflammatory diseases and glioblastoma. Despite several attempts, no validated CSF-1R PET tracer is currently available. The aim of this work was to develop a brain permeable CSF-1R PET tracer for non-invasive imaging of CSF-1R in vivo. Based on fragments of two potent and selective CSF-1R inhibitors, novel hybrid molecules were designed and synthesized. Affinity for human recombinant CSF-1R and selectivity over c-KIT and PDGFR-β was determined using a FRET based in vitro assay. Radiosynthesis was performed by fully automated [ 11 C]CH 3 I methylation of the corresponding des-methyl precursor. PET imaging was performed at baseline, efflux transporter blocking and CSF-1R blocking conditions. Moreover, tracer distribution and blood and plasma radiometabolites were determined following injection in healthy mice. The most promising CSF-1R inhibitor, compound 4, showed high selectivity and high affinity for CSF-1R (IC 50 : 12 ± 3 nM) and no affinity for kinase family members c-KIT and PDGFR-beta. [ 11 C]4 was obtained in good yield (15 ± 0.2 % decay corrected yield, (2.0 ± 0.26 GBq at end of synthesis) and excellent purity. The compound demonstrated high brain penetration and good metabolic stability (>2 %ID/g at 60 min post injection and 79 ± 8 % intact [ 11 C]4 in brain at 60 min post injection) and no strong efflux transporter substrate behavior. Blocking CSF-1R prior to imaging with [ 11 C]4 resulted in significant decrease in brain uptake. In conclusion, [ 11 C]4 shows good potential as a novel PET tracer for imaging of CSF-1R in the CNS and future experiments in relevant animal models are warranted.
Competing Interests: Declaration of competing interest There are no competing interests to report.
(Copyright © 2022. Published by Elsevier Inc.)
Databáze: MEDLINE
Externí odkaz: