In Vitro Evaluation of [3H]CPPC as a Tool Radioligand for CSF-1R

Microglia play a role in several central nervous system (CNS) diseases and are a highly sought target for positron emission tomography (PET) imaging and therapeutic intervention. 5-Cyano-N-(4-(4-[11C]­methylpiperazin-1-yl)-2-(piperidin-1-yl)­phenyl)­furan-2-carboxamide ([11C]­CPPC) is a radiopharmac...

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Bibliographic Details
Published in:ACS chemical neuroscience 2021-03, Vol.12 (6), p.998-1006
Main Authors: Knight, Ashley C, Varlow, Cassis, Zi, Tong, Liang, Steven H, Josephson, Lee, Schmidt, Karl, Patel, Shil, Vasdev, Neil
Format: Article
Language:English
Subjects:
Animals
Autoradiography
Microglia
Positron-Emission Tomography
Radiopharmaceuticals
Receptor Protein-Tyrosine Kinases
Rodentia
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Summary:Microglia play a role in several central nervous system (CNS) diseases and are a highly sought target for positron emission tomography (PET) imaging and therapeutic intervention. 5-Cyano-N-(4-(4-[11C]­methylpiperazin-1-yl)-2-(piperidin-1-yl)­phenyl)­furan-2-carboxamide ([11C]­CPPC) is a radiopharmaceutical designed to selectively target microglia via macrophage colony stimulating factor-1 receptor (CSF-1R) in the CNS. Herein, we report the first preclinical evaluation of [3H]­CPPC using radioligand binding methods for the evaluation of putative CSF-1R inhibitors in rodent models of neuroinflammation. The distribution of [3H]­CPPC by autoradiography did not align with 18 kDa translocator protein (TSPO) distribution using [3H]­PBR28 and IBA-1 staining for microglia. In the CNS, [3H]­CPPC had considerable nonspecific binding, as indicated by a low displacement of the tritiated ligand by unlabeled CPPC and the known CSF1R inhibitors BLZ-945 and PLX3397. Spleen was identified as a tissue that provided an adequate signal-to-noise ratio to enable screening with [3H]­CPPC and a library of 20 novel PLX3397 derivatives. However, unlabeled CPPC lacked selectivity and showed off-target binding to a substantial number of kinase targets (204 out of 403 tested) at a concentration relevant to in vitro radioligand binding assays (10 μM). These findings suggest that, while [3H]­CPPC may have utility as a radioligand tool for the evaluation of peripheral targets and screening of CSF-1R inhibitors, it may have limited utility as an in vivo CNS imaging probe on the basis of the current evaluation.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.0c00802