Synthesis and Initial In Vivo Evaluation of [11C]AZ683-A Novel PET Radiotracer for Colony Stimulating Factor 1 Receptor (CSF1R).

Peter Scott,Andrew Mossine,Janna Arteaga,Sean Tanzey,Jenelle Stauff,Xia Shao,Phillip Sherman

doi:10.3390/ph11040136

Abstract

Positron emission tomography (PET) imaging of Colony Stimulating Factor 1 Receptor (CSF1R) is a new strategy for quantifying both neuroinflammation and inflammation in the periphery since CSF1R is expressed on microglia and macrophages. AZ683 has high affinity for CSF1R (Ki = 8 nM; IC50 = 6 nM) and >250-fold selectivity over 95 other kinases. In this paper, we report the radiosynthesis of [11C]AZ683 and initial evaluation of its use in CSF1R PET. [11C]AZ683 was synthesized by 11C-methylation of the desmethyl precursor with [11C]MeOTf in 3.0% non-corrected activity yield (based upon [11C]MeOTf), >99% radiochemical purity and high molar activity. Preliminary PET imaging with [11C]AZ683 revealed low brain uptake in rodents and nonhuman primates, suggesting that imaging neuroinflammation could be challenging but that the radiopharmaceutical could still be useful for peripheral imaging of inflammation.

Highlights

Colony Stimulating Factor 1 Receptor (CSF1R, M-CSF, or cFMS) is a class III receptor tyrosine kinase [1] that regulates immune response by controlling the survival and activity of macrophages and macrophage-like cells [2]
Chronic inflammation caused by increased activity of macrophages due to increased CSF1R response is present in many autoimmune disorders such as rheumatoid arthritis, inflammatory bowel disease, and autoimmune nephritis, among others [4,5]
Low receptor density would not limit first pass brain influx and efflux which was quite low. Overall these Positron emission tomography (PET) imaging data suggest imaging CSF1R associated with neuroinflammation using [11C]AZ683 may be challenging, but that uptake in monkey could be sufficient to observe accumulation in a brain inflammation model

Summary

Introduction

Colony Stimulating Factor 1 Receptor (CSF1R, M-CSF, or cFMS) is a class III receptor tyrosine kinase [1] that regulates immune response by controlling the survival and activity of macrophages and macrophage-like cells [2]. Low receptor density would not limit first pass brain influx and efflux which was quite low Overall these PET imaging data suggest imaging CSF1R associated with neuroinflammation using [11C]AZ683 may be challenging, but that uptake in monkey could be sufficient to observe accumulation in a brain inflammation model. As we take a conservative view towards primate safety, methods to determine whether efflux activity is responsible for the low brain uptake of [11C]AZ683 (e.g., cyclosporin A blockade of the P-gp transporter [34]) have not been pursued at this time In this case, cLogP estimates (Table 1) may not be a good indicator of BBB permeability. HH--bboonndd aacccceeppttoorrss RRoottaattaabbllee bboonnddss MMeettaabboolliicc ssttaabbiilliittyy PharmccaLLceoouSStggioocPPallpplu—u—sKKbb2((0iiaaNNll1ii8tt,yy++11OO, 1))

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Compounds Synthesized

General Considerations

Animal Husbandry and Housing

Rodent Imaging Protocol

Primate Imaging Protocol

PET Image Analysis

Findings

Conclusions