Re(CO)([F]FEDA)，一种新型 F PET 肾示踪剂：放射性合成与临床前评估。
Re(CO)([F]FEDA), a novel F PET renal tracer: Radiosynthesis and preclinical evaluation.
机构信息
Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, NE, Atlanta, GA 30322, USA.
Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, NE, Atlanta, GA 30322, USA.
出版信息
Nucl Med Biol. 2018 Mar;58:42-50. doi: 10.1016/j.nucmedbio.2017.12.001. Epub 2017 Dec 27.
INTRODUCTION
Our previous work demonstrated that the Tc renal tracer, Tc(CO)(FEDA) (Tc-1), has a rapid clearance comparable in rats to that of I-OIH, the radioactive gold standard for the measurement of effective renal plasma flow. The uncharged fluoroethyl pendant group of Tc-1 provides a route to the synthesis of a structurally analogous rhenium-tricarbonyl F renal imaging agent, Re(CO)([F]FEDA) (F-1). Our goal was to develop an efficient one-step method for the preparation of F-1 and to compare its pharmacokinetic properties with those of I-OIH in rats.
METHODS
F-1 was prepared by the nucleophilic F-fluorination of its tosyl precursor. The labeled compound was isolated by HPLC and subsequently evaluated in Sprague-Dawley rats using I-OIH as an internal control and by dynamic PET/CT imaging. Plasma protein binding (PPB) and erythrocyte uptake (RCB) were determined and the urine was analyzed for metabolites.
RESULTS
F-1 was efficiently prepared as a single species with high radiochemical purity (>99%) and it displayed high radiochemical stability in vitro and in vivo. PPB was 87% and RCB was 21%. Biodistribution studies confirmed rapid renal extraction and high specificity for renal excretion, comparable to that of I-OIH, with minimal hepatic/gastrointestinal elimination. The activity in the urine, as a percentage of I-OIH, was 92% and 95% at 10 and 60 min, respectively. All other organs (heart, spleen, lungs) showed a negligible tracer uptake (<0.4% ID). Dynamic microPET/CT imaging demonstrated rapid transit of F-1 through the kidneys and into the bladder; there was no demonstrable activity in bone verifying the absence of free [F]fluoride.
CONCLUSIONS
F-1 exhibited a high specificity for the kidney, rapid renal excretion comparable to that of I-OIH and high in vivo radiochemical stability. Not only is F-1 a promising PET renal tracer, but it provides a route to the development of a pair of analogous F/Tc renal imaging agents with almost identical structures and comparable pharmacokinetic properties. These promising in vivo results warrant subsequent evaluation in humans.
简介
我们之前的工作表明，Tc 肾示踪剂 Tc(CO)(FEDA)（Tc-1）在大鼠体内的清除速度与放射性金标准碘[131I]碘代油（I-OIH）相当，可用于测量有效肾血浆流量。Tc-1 中不带电荷的氟乙基侧链为合成结构类似的三价 Re 碳酰氟基 F 肾成像剂 Re(CO)([F]FEDA)（F-1）提供了一种途径。我们的目标是开发一种高效的一步法来制备 F-1，并比较其在大鼠体内的药代动力学特性与 I-OIH 的特性。
方法
通过亲核 F-氟代其 tosyl 前体来制备 F-1。通过 HPLC 分离标记化合物，随后使用 I-OIH 作为内对照，通过动态 PET/CT 成像在 Sprague-Dawley 大鼠中进行评估。测定血浆蛋白结合率（PPB）和红细胞摄取率（RCB），并分析尿液中的代谢物。
结果
F-1 可高效制备为单一物种，放射化学纯度>99%，体外和体内均显示出高放射化学稳定性。PPB 为 87%，RCB 为 21%。生物分布研究证实，其快速的肾脏摄取和高特异性肾排泄与 I-OIH 相当，肝/胃肠道清除最小。在 10 和 60 分钟时，尿液中 F-1 的活性分别为 I-OIH 的 92%和 95%。所有其他器官（心、脾、肺）的示踪剂摄取均<0.4% ID。动态 microPET/CT 成像显示 F-1 迅速通过肾脏进入膀胱；骨骼中未检测到游离[F]氟，证明不存在游离[F]氟。
结论
F-1 对肾脏具有高度特异性，肾脏排泄速度与 I-OIH 相当，体内放射化学稳定性高。F-1 不仅是一种有前途的 PET 肾示踪剂，而且还为开发一对具有几乎相同结构和可比药代动力学特性的类似 F/Tc 肾成像剂提供了途径。这些有前途的体内结果证明了在人类中的后续评估是合理的。
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