Synthesis of 11C-labeled DNA polymerase-ß inhibitor 5-methoxyflavone and PET/CT imaging thereof.
Nucl Med Biol
; 78-79: 17-22, 2019.
Article
in En
| MEDLINE
| ID: mdl-31678783
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-ß 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-ß 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% (nâ¯=â¯3) with a radiochemical purity >99%. The average molar radioactivity of 5-[11C]methoxyflavone was 383â¯GBq/µmol. The average concentration was 0.107⯵g/mL. PET/CT imaging in mice showed 5-[11C]methoxyflavone rapidly passed through the blood-brain barrier with 8.36⯱â¯0.61%ID/g at 2â¯min post injection, and the radioactivity accumulation in brain was still noticeable with 2.48⯱â¯0.59%ID/g at 28â¯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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carbon Radioisotopes
/
DNA Polymerase beta
/
Flavones
/
Positron Emission Tomography Computed Tomography
Limits:
Animals
Language:
En
Journal:
Nucl Med Biol
Journal subject:
BIOLOGIA
/
MEDICINA NUCLEAR
Year:
2019
Type:
Article
Affiliation country:
China