Chong Yan, Chang Jin, Zhao Wenwen, He Yong, Li Yuqiao, Zhang Huabei, Qi Chuanmin
Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University, Beijing, People's Republic of China.
J Labelled Comp Radiopharm. 2018 Feb;61(2):42-53. doi: 10.1002/jlcr.3538. Epub 2018 Feb 2.
Four novel F-labeled quinazoline derivatives with low lipophilicity, [ F]4-(2-fluoroethoxy)-6,7-dimethoxyquinazoline ([ F]I), [ F]4-(3-((4-(2-fluoroethoxy)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine ([ F]II), [ F]4-(2-fluoroethoxy)-7-methoxy-6-(2-methoxyethoxy)quinazoline ([ F]III), and [ F]4-(2-fluoroethoxy)-6,7-bis(2-methoxyethoxy)quinazoline ([ F]IV), were synthesized via a 2-step radiosynthesis procedure with an overall radiochemical yield of 10% to 38% (without decay correction) and radiochemical purities of >98%. The lipophilicity and stability of labeled compounds were tested in vitro. The log P values of the 4 radiotracers ranged from 0.52 to 1.07. We then performed ELISA to measure their affinities to EGFR-TK; ELISA assay results indicated that each inhibitor was specifically bounded to EGFR-TK in a dose-dependent manner. The EGFR-TK autophosphorylation IC values of [ F]I, [ F]II, [ F]III, and [ F]IV were 7.732, 0.4698, 0.1174, and 0.1176 μM, respectively. All labeled compounds were evaluated via cellular uptake and blocking studies in HepG2 cell lines in vitro. Cellular uptake and blocking experiment results indicated that [ F]I and [ F]III had excellent cellular uptake at 120-minute postinjection in HepG2 carcinoma cells (51.80 ± 3.42%ID/mg protein and 27.31 ± 1.94%ID/mg protein, respectively). Additionally, biodistribution experiments in S180 tumor-bearing mice in vivo indicated that [ F]I had a very fast clearance in blood and a relatively high uptake ratio of tumor to blood (4.76) and tumor to muscle (1.82) at 60-minute postinjection. [ F]III had a quick clearance in plasma, and its highest uptake ratio of tumor to muscle was 2.55 at 15-minute postinjection. These experimental results and experiences were valuable for the further exploration of novel radiotracers of quinazoline derivatives.
四种新型低亲脂性的F标记喹唑啉衍生物，[F]4-(2-氟乙氧基)-6,7-二甲氧基喹唑啉([F]I)、[F]4-(3-((4-(2-氟乙氧基)-7-甲氧基喹唑啉-6-基)氧基)丙基)吗啉([F]II)、[F]4-(2-氟乙氧基)-7-甲氧基-6-(2-甲氧基乙氧基)喹唑啉([F]III)和[F]4-(2-氟乙氧基)-6,7-双(2-甲氧基乙氧基)喹唑啉([F]IV)，通过两步放射性合成程序合成，总放射化学产率为10%至38%（未进行衰变校正），放射化学纯度>98%。对标记化合物的亲脂性和稳定性进行了体外测试。这4种放射性示踪剂的log P值范围为0.52至1.07。然后进行ELISA以测量它们对EGFR-TK的亲和力；ELISA测定结果表明，每种抑制剂均以剂量依赖性方式特异性结合到EGFR-TK上。[F]I、[F]II、[F]III和[F]IV的EGFR-TK自磷酸化IC值分别为7.732、0.4698、0.1174和0.1176 μM。所有标记化合物均通过体外HepG2细胞系的细胞摄取和阻断研究进行评估。细胞摄取和阻断实验结果表明，[F]I和[F]III在注射后120分钟时在HepG2癌细胞中具有优异的细胞摄取（分别为51.80±3.42%ID/mg蛋白和27.31±1.94%ID/mg蛋白）。此外，在荷S180肿瘤小鼠体内进行的生物分布实验表明，[F]I在血液中的清除非常快，在注射后60分钟时肿瘤与血液的摄取比相对较高（4.76），肿瘤与肌肉的摄取比为1.82。[F]III在血浆中的清除较快，其在注射后15分钟时肿瘤与肌肉的最高摄取比为2.55。这些实验结果和经验对于进一步探索新型喹唑啉衍生物放射性示踪剂具有重要价值。
