Zude Chen1, Xiashuang Wang2, Yulong Xu3, Changning Wang4. 1. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Guoxue Xiang 37, Chengdu 610041, China. 2. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States. 3. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States. Electronic address: Yulong.Xu@mgh.harvard.edu. 4. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States. Electronic address: cwang15@mgh.harvard.edu.
Abstract
INTRODUCTION: "Cell-cycle hypothesis" is emerging in recent years to suggest that aberrant cell cycle re-entry of differentiated neurons leads to a remarkable genetic disequilibrium which is likely to be the primary cause of neuronal apoptosis. DNA polymerase-β is involved in neuronal DNA replication during cell cycle re-entry, thus constituting a promising target for Alzheimer's disease treatment. Recently, 5-methoxyflavone was identified as a candidate molecule endowed with good biological activity and selectivity on the DNA pol-β in multiple in vitro AD models. In vivo assays, especially the brain uptake of 5-methoxyflavone, is need to be evaluated for further development for AD treatment. We report herein the synthesis of 11C-labeled 5-methoxyflavone, and the evaluation of in vivo properties of 5-[11C]methoxyflavone in rodents. METHODS: The strategy for synthesis of 5-[11C]methoxyflavone was developed by treating precursor 5-hydroxyflavone with [11C]CH3I and KOH in anhydrous DMF. 5-[11C]Methoxyflavone was purified, then evaluated in mice by using PET/CT imaging. RESULTS: The 5-[11C]methoxyflavone was synthesized conveniently in an average decay corrected yield of 22% (n = 3) with a radiochemical purity >99%. The average molar radioactivity of 5-[11C]methoxyflavone was 383 GBq/μmol. The average concentration was 0.107 μg/mL. PET/CT imaging in mice showed 5-[11C]methoxyflavone rapidly passed through the blood-brain barrier with 8.36 ± 0.61%ID/g at 2 min post injection, and the radioactivity accumulation in brain was still noticeable with 2.48 ± 0.59%ID/g at 28 min post injection. The clearance rate was 3.37 (brain2 min/brain28 min ratio). The blood and muscle uptakes were low. The lung displayed high initial uptake and subsequent rapid clearance, while the liver and kidney displayed a relatively slow clearance. Real-time imaging showed that 5-[11C]methoxyflavone accumulated immediately in the heart, then transferred to the liver and intestine, and was not observed in lower digestive tract. CONCLUSIONS: 5-[11C]Methoxyflavone was synthesized conveniently in one step. The results of PET/CT imaging in C57BL/6 mice suggested 5-[11C]methoxyflavone possesses appropriate pharmacokinetic properties and favorable brain uptake, thus being proved to be suitable for further development for AD treatment.
INTRODUCTION: "Cell-cycle hypothesis" is emerging in recent years to suggest that aberrant cell cycle re-entry of differentiated neurons leads to a remarkable genetic disequilibrium which is likely to be the primary cause of neuronal apoptosis. DNA polymerase-β is involved in neuronal DNA replication during cell cycle re-entry, thus constituting a promising target for Alzheimer's disease treatment. Recently, 5-methoxyflavone was identified as a candidate molecule endowed with good biological activity and selectivity on the DNA pol-β in multiple in vitro AD models. In vivo assays, especially the brain uptake of 5-methoxyflavone, is need to be evaluated for further development for AD treatment. We report herein the synthesis of 11C-labeled 5-methoxyflavone, and the evaluation of in vivo properties of 5-[11C]methoxyflavone in rodents. METHODS: The strategy for synthesis of 5-[11C]methoxyflavone was developed by treating precursor 5-hydroxyflavone with [11C]CH3I and KOH in anhydrous DMF. 5-[11C]Methoxyflavone was purified, then evaluated in mice by using PET/CT imaging. RESULTS: The 5-[11C]methoxyflavone was synthesized conveniently in an average decay corrected yield of 22% (n = 3) with a radiochemical purity >99%. The average molar radioactivity of 5-[11C]methoxyflavone was 383 GBq/μmol. The average concentration was 0.107 μg/mL. PET/CT imaging in mice showed 5-[11C]methoxyflavone rapidly passed through the blood-brain barrier with 8.36 ± 0.61%ID/g at 2 min post injection, and the radioactivity accumulation in brain was still noticeable with 2.48 ± 0.59%ID/g at 28 min post injection. The clearance rate was 3.37 (brain2 min/brain28 min ratio). The blood and muscle uptakes were low. The lung displayed high initial uptake and subsequent rapid clearance, while the liver and kidney displayed a relatively slow clearance. Real-time imaging showed that 5-[11C]methoxyflavone accumulated immediately in the heart, then transferred to the liver and intestine, and was not observed in lower digestive tract. CONCLUSIONS:5-[11C]Methoxyflavone was synthesized conveniently in one step. The results of PET/CT imaging in C57BL/6 mice suggested 5-[11C]methoxyflavone possesses appropriate pharmacokinetic properties and favorable brain uptake, thus being proved to be suitable for further development for AD treatment.
Authors: Yulong Xu; Yiming Xu; Hallie Blevins; Yu Lan; Yan Liu; Gengyang Yuan; Robin Striar; Julia S Zagaroli; Darcy R Tocci; Amelia G Langan; Can Zhang; Shijun Zhang; Changning Wang Journal: Bioorg Med Chem Lett Date: 2021-01-06 Impact factor: 2.823