Evaluation of carbon-11 labeled 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide as PET tracer for imaging of CSF-1R expression in the brain
| العنوان: | Evaluation of carbon-11 labeled 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide as PET tracer for imaging of CSF-1R expression in the brain |
|---|---|
| المؤلفون: | Bin Shen, Esther J.M. Kooijman, Albert D. Windhorst, Frederick T. Chin, Madina Nezam, Samantha T. Reyes, Berend van der Wildt |
| المساهمون: | Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging |
| المصدر: | Bioorganic and Medicinal Chemistry, 42:116245. Elsevier Limited van der Wildt, B, Nezam, M, Kooijman, E J M, Reyes, S T, Shen, B, Windhorst, A D & Chin, F T 2021, ' Evaluation of carbon-11 labeled 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide as PET tracer for imaging of CSF-1R expression in the brain ', Bioorganic and Medicinal Chemistry, vol. 42, 116245 . https://doi.org/10.1016/j.bmc.2021.116245Test |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Tariquidar, Clinical Biochemistry, Pharmaceutical Science, Receptor, Macrophage Colony-Stimulating Factor, Pharmacology, 01 natural sciences, Biochemistry, Colony stimulating factor 1 receptor, chemistry.chemical_compound, Drug Discovery, medicine, Animals, Carbon Radioisotopes, Molecular Biology, IC50, Trifluoromethyl, Nicotinamide, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, Radiosynthesis, Brain, In vitro, 0104 chemical sciences, Rats, 010404 medicinal & biomolecular chemistry, Positron-Emission Tomography, Molecular Medicine, Ex vivo, medicine.drug |
| الوصف: | Pharmacological targeting of tumor associated macrophages and microglia in the tumor microenvironment is a novel therapeutic strategy in the treatment of glioblastoma multiforme. As such, the colony stimulating factor-1 receptor (CSF-1R) has been identified as a druggable target. However, no validated companion diagnostic marker for these therapies exists to date. Towards development of a CSF-1R PET tracer, a set of six compounds based on recently reported CSF-1R inhibitor 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide (Compound 5) was designed, synthesized and evaluated in vitro for potency and selectivity. The highest affinity for CSF-1R was found for compound 5 (IC50: 2.7 nM). Subsequent radiosynthesis of [11C]5 was achieved in 2.0 ± 0.2% yield (decay corrected to start of synthesis) by carbon-11 carbon monoxide aminocarbonylation in 40 min after end of bombardment. In vitro autoradiography with [11C]5 on rat brain sections demonstrated high specific binding, but also strong off-target binding. Ex vivo, only intact tracer was observed in blood plasma at 90 min post injection in healthy rats. PET scanning results demonstrated negligible brain uptake under baseline conditions and this brain uptake did not increase by blocking of efflux transporters using Tariquidar. To conclude, [11C]5 was successfully synthesized and evaluated in healthy rats. However, the inability of [11C]5 to cross the blood-brain-barrier excludes its use for imaging of CSF-1R expression in the brain. |
| وصف الملف: | application/vnd.openxmlformats-officedocument.wordprocessingml.document |
| تدمد: | 1464-3391 0968-0896 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3d6407f64f503e7d9f00f9d31aa43890Test https://pubmed.ncbi.nlm.nih.gov/34119698Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3d6407f64f503e7d9f00f9d31aa43890 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14643391 09680896 |
|---|