RATIONALE Novel bifunctional compounds composed of a caffeine scaffold attached to nicotine (C8 -6-N), 1-aminoindan (C8 -6-I), or caffeine (C8 -6-C8 ) were designed as therapeutics or diagnostics for Parkinson's disease (PD). In order to probe their pharmacological and toxicological profile, an appropriate analytical method is required. The goal of this study is to establish a tandem mass spectrometric fingerprint for the development of quantitative and qualitative methods that will aid future assessment of the in vitro and in vivo absorption, distribution, metabolism, excretion (ADME) and pharmacokinetic properties of these lead bifunctional compounds for PD. METHODS Accurate mass measurement was performed using a hybrid quadrupole orthogonal time-of-flight mass spectrometer while multistage MS/MS and MS3 analyses were conducted using a triple quadrupole linear ion trap mass spectrometer. Both instruments are equipped with an electrospray ionization (ESI) source and were operated in the positive ion mode. The source and compound parameters were optimized for all three tested bifunctional compounds. RESULTS The MS/MS analysis indicates that the fragmentation of C8 -6-N and C8 -6-I is driven by the dissociation of the nicotine and 1-aminoindan moieties, respectively, but not caffeine. A significant observation in the MS/MS fragmentation of C8 -6-C8 suggests that a previously reported loss of acetaldehyde during caffeine dissociation is instead a loss of CO2 . CONCLUSIONS The collision-induced tandem mass spectrometry (CID-MS/MS) analysis of these novel bifunctional compounds revealed compound-specific diagnostic product ions and neutral losses for all three tested bifunctional compounds. The established MS/MS fingerprint will be applied to the future development of qualitative and quantitative methods.

中文翻译：

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新型基于咖啡因支架的双功能化合物对帕金森氏病的串联质谱分析。

新型双功能化合物由连接至尼古丁（C8 -6-N），1-氨基茚满（C8 -6-I）或咖啡因（C8 -6-C8）的咖啡因支架组成，被设计为帕金森氏病（ PD）。为了探究其药理和毒理特性，需要一种适当的分析方法。这项研究的目的是建立一种串联质谱指纹图谱，以开发定量和定性方法，以帮助将来评估这些双功能铅的体外和体内吸收，分布，代谢，排泄（ADME）和药代动力学特性。 PD的化合物。方法使用混合四极杆正交飞行时间质谱仪进行准确的质量测量，同时使用三重四极杆线性离子阱质谱仪进行多级MS / MS和MS3分析。两种仪器均配备了电喷雾电离（ESI）源，并以正离子模式运行。对于所有三种测试的双功能化合物，均优化了来源和化合物参数。结果MS / MS分析表明，C8 -6-N和C8 -6-I的片段化分别是由烟碱和1-氨基茚满部分的解离驱动的，而不是由咖啡因的解离驱动的。在C8 -6-C8的MS / MS碎片中的一个重要观察结果表明，先前报道的咖啡因解离过程中乙醛的损失是CO2的损失。结论对这些新型双功能化合物的碰撞诱导串联质谱（CID-MS / MS）分析显示了所有三种测试的双功能化合物的化合物特异性诊断产物离子和中性损失。建立的MS / MS指纹将用于定性和定量方法的未来发展。