基于 ICI 89,406 的 18F 标记β1-肾上腺素能受体选择性放射性配体的临床前评价。
Preclinical evaluation of an 18F-labelled beta1-adrenoceptor selective radioligand based on ICI 89,406.
机构信息
Department of Nuclear Medicine, University Hospital Münster, D-48149 Münster, Germany.
出版信息
Nucl Med Biol. 2010 May;37(4):517-26. doi: 10.1016/j.nucmedbio.2010.01.004.
PURPOSE
Radioligand binding studies indicate a down-regulation of myocardial beta(1)-adrenoceptors (beta(1)-AR) in cardiac disease which may or may not be associated with a decrease in beta(2)-ARs. We have chosen ICI 89,406, a beta(1)-selective AR antagonist, as the lead structure to develop new beta(1)-AR radioligands for PET and have synthesised a fluoro-ethoxy derivative (F-ICI).
METHODS
(S)-N-[2-[3-(2-Cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]-N'-[4-(2-[(18)F]fluoro-ethoxy)-phenyl]-urea ((S)-[(18)F]F-ICI) was synthesised. Myocardial uptake of radioactivity after intravenous injection of (S)-[(18)F]F-ICI into adult CD(1) mice or Wistar rats was assessed with positron emission tomography (PET) and postmortem dissection. Metabolism was assessed by high-performance liquid chromatography analysis of plasma and urine.
RESULTS
The heart was visualised with PET after injection of (S)-[(18)F]F-ICI but neither unlabelled F-ICI nor propranolol (non-selective beta-AR antagonist) injected 15 min after (S)-[(18)F]F-ICI affected myocardial radioactivity. Ex vivo dissection demonstrated that predosing with propranolol or CGP 20712 (beta(1)-selective AR-antagonist) did not affect myocardial radioactivity. Radiometabolites rapidly appeared in plasma and both (S)-[(18)F]F-ICI and radiometabolites accumulated in urine.
CONCLUSIONS
Myocardial uptake of (S)-[(18)F]F-ICI after intravenous injection was mainly at sites unrelated to beta(1)-ARs. (S)-[(18)F]F-ICI is not a suitable beta(1)-selective-AR radioligand for PET.
目的
放射性配体结合研究表明，在心脏疾病中，心肌β1-肾上腺素能受体（β1-AR）的表达下调，这可能与β2-AR 的减少有关，也可能无关。我们选择 ICI 89,406，一种β1-选择性 AR 拮抗剂，作为开发用于正电子发射断层扫描（PET）的新型β1-AR 放射性配体的先导结构，并合成了一种氟乙氧基衍生物（F-ICI）。
方法
合成了（S）-N-[2-[3-（2-氰基苯氧基）-2-羟基丙氨基]-乙基]-N'-[4-（2-[(18)F]氟乙氧基）-苯基]-脲（（S）-[(18)F]F-ICI）。通过正电子发射断层扫描（PET）和死后解剖评估静脉注射（S）-[(18)F]F-ICI 后成年 CD1 小鼠或 Wistar 大鼠心脏的放射性摄取。通过高效液相色谱法分析血浆和尿液来评估代谢。
结果
注射（S）-[(18)F]F-ICI 后可通过 PET 观察到心脏，但在注射（S）-[(18)F]F-ICI 15 分钟后注射未标记的 F-ICI 或普萘洛尔（非选择性β-AR 拮抗剂）均不影响心肌放射性。离体解剖显示，用普萘洛尔或 CGP 20712（β1-选择性 AR 拮抗剂）预给药不影响心肌放射性。放射性代谢物迅速出现在血浆中，（S）-[(18)F]F-ICI 和放射性代谢物均在尿液中积累。
结论
静脉注射后，（S）-[(18)F]F-ICI 在心脏中的摄取主要发生在与β1-AR 无关的部位。（S）-[(18)F]F-ICI 不是用于 PET 的合适的β1-选择性 AR 放射性配体。
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