RT Journal Article SR Electronic T1 Synthesis of 11C-labeled DNA polymerase-β inhibitor 5-methoxyflavone and PET/CT imaging thereof JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 150 OP 150 VO 61 IS supplement 1 A1 Yulong Xu A1 Zude Chen A1 Xiashuang Wang A1 Changning Wang YR 2020 UL http://jnm.snmjournals.org/content/61/supplement_1/150.abstract AB 150Background: Alzheimer's disease (AD) imposes a huge economic burden and induces an unbearable psychological pressure, thus being a major reason for concern for society and a topic for intensive research. According to “cell-cycle hypothesis”, only partial DNA replication can be performed by postmitotic neurons which have resumed cell cycle, while the cell division can’t be completed, thus leading to a remarkable genetic disequilibrium which is likely to be the primary cause of neuronal apoptosis. Experimental evidence is accumulating to suggest that neuronal DNA replication during cell cycle re-entry is carried out by DNA polymerase-β (DNA pol-β). DNA pol-β, therefore, constitutes a promising target for AD treatment. Objective: 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. However, in vivo assays, especially the brain uptake of 5-methoxyflavone, were not examined. To investigate the in vivo properties of 5-methoxyflavone, 11C-labeled 5-methoxyflavone needs to be developed, and the distribution of 5-[11C]methoxyflavone in rodent brain needs to be evaluated by PET/CT imaging. Method: 5-[11C]methoxyflavone was radiolabeled in one step by treating precursor 5-hydroxyflavone with [11C]CH3I and KOH in anhydrous DMF at 100 °C for 3 min and was purified by high-performance liquid chromatography (HPLC). Then, in vivo PET/CT imaging was conducted to evaluate the biodistribution of 5-[11C]methoxyflavone in mice. Results: The 5-[11C]methoxyflavone was synthesized conveniently in an average decay corrected yield of 22% (n = 3) with a radiochemical purity greater than 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. Conclusion: 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.