中枢多巴胺系统正电子发射计算机断层扫描显像剂的研究进展

中枢多巴胺系统与多种神经行为障碍的病理生理学有关。一直以来,多巴胺系统正电子发射计算机断层扫描(PET)成像在研究活体大脑中多巴胺生物化学过程上有着重要价值。PET成像的基础是¹¹C、¹⁸F等发射正电子的放射性核素标记的显像剂,这些显像剂通过与多巴胺神经系统不同的靶点特异性结合从而反映多巴胺合成、囊泡储存、突触释放和受体结合以及再摄取过程,推动神经病学、精神病学、药物滥用和成瘾以及药物开发的研究进展。本文综述了以氨基酸脱羧酶、多巴胺转运体、多巴胺受体以及囊泡单胺转运体为靶点的¹¹C、¹⁸F标记的PET显像剂的研究进展。     

Tc标记的叶酸肿瘤显像剂

叶酸受体在许多源于上皮组织的恶性肿瘤中高度表达,是目前肿瘤放射性显像研究的一个新的靶点。由于叶酸对于叶酸受体具有很高的亲和性,作为重要的特异性靶向介导分子,^99mTc标记叶酸肿瘤显像剂已成为当前放射性药物的研究热点之一。本文对不同类型的^99mTc标记的叶酸类放射性肿瘤显像剂的研究进展、应用情况和存在的问题进行了评述,探讨了^99mTc标记叶酸显像剂的一般设计方法,并对其未来发展方向进行了展望。     

PET心肌灌注显像剂

由于PET在心肌灌注显像方面具有高分辨率、高灵敏度、低组织衰减和心肌血流定量等优势而使得PET心肌灌注显像剂的研究日益受到关注。本文介绍了目前已经应用于临床的PET心肌灌注显像剂的情况,分别综述了 ¹⁸F 标记和其他正电子核素标记的PET心肌灌注显像剂的研究进展,重点讨论了几种亲脂性阳离子类和线粒体复合物Ⅰ(MC-Ⅰ)抑制剂类 ¹⁸F 标记心肌灌注显像剂,特别是近年取得突破性进展的MC-Ⅰ抑制剂类心肌灌注显像剂(如BMS-747158-02和[¹⁸F]FP1OP),介绍了各类PET心肌灌注显像剂的生物性能、心肌摄取机制,对其优缺点进行比较,并对PET心肌灌注显像剂的应用前景进行了展望。     

正电子发射断层显像剂[18F]FET前体N-叔丁氧羰基-O-(2-三氟甲磺酰氧乙基)-L-酪氨酸甲酯/叔丁酯的合成

本文合成了正电子发射断层显像剂[¹⁸F]FET的两个新型前体：N-叔丁氧羰基-O-(2-三氟甲磺酰氧乙基)-L-酪氨酸甲酯9a和N-叔丁氧羰基-O-(2-三氟甲磺酰氧乙基)-L-酪氨酸叔丁酯9b. 化合物9a或9b以L-酪氨酸为原料, 先与甲醇发生酯化反应或与乙酸叔丁酯进行酯交换, 再用叔丁氧羰基保护氨基, 接着在苯环的酚羟基上引入羟乙基, 最后与三氟甲磺酸酐反应形成目标化合物, 这四步反应总收率分别是30%或15%.     

阴离子Gemini表面活性剂和阳离子传统表面活性剂混合体系双水相中囊泡形貌的转变

通过电子显微镜观察了阴离子gemini表面活性剂C₁₁- p-PhCNa和阳离子传统表面活性剂DTAB混合体系双水相中囊泡形貌随体系组成和浓度的转变。结果表明,双水相较浓的一相中形成了多层囊泡,囊泡的大小和壁厚随相的组成和浓度而改变,两组分等电荷混合有利于形成较大且壁较厚的囊泡。分析表明, gemini表面活性剂在聚集体中采取的反式构象可能是其容易形成厚壁多层囊泡的重要原因,C₁₁- p-PhCNa联接链上的苯氧基与DTA⁺之间的p-阳离子相互作用以及两组分相反电性头基之间的静电吸引使囊泡壁的多层结构更加稳定。     

高效液相色谱-化学发光方法同时测定血清中的肾上腺素、去甲肾上腺素和多巴胺

本文基于肾上腺素、去甲肾上腺素和多巴胺对鲁米诺-铁氰化钾化学发光体系的增敏作用，建立了一种高效液相色谱分离-化学发光检测体系同时检测三种物质；研究了试剂浓度、酸碱条件、流动相成分等参数对分析结果的影响。在优化发光条件下，以邻苯二甲酸氢钾-甲醇溶液（92：8）为色谱流动相，用C₁₈柱分离检测肾上腺素、去甲肾上腺素和多巴胺样品，肾上腺素线性范围为1×10^-8~5×10^-6g/mL，检测限4.0×10^-9g/mL；去甲肾上腺素线性范围是 5.0×10^-9~1.0×10^-6g/mL，检测限1.0×10^-9g/mL；多巴胺线性范围为5.0×10^-9~1.0×10^-6g/mL，检测限8.0×10^-10g/mL。本方法快速、简便而准确，且已成功用于血清中三种物质的分析。     

5-羟色胺转运蛋白显像剂的研究进展

中枢神经系统5-羟色胺神经元功能异常,特别是突触前膜的5-羟色胺转运蛋白（SERT）密度的变化常导致复杂的精神紊乱疾病。SERT的正电子发射断层（PET）和单光子发射断层（SPECT）活体显像剂有助于研究该系统的变化与精神紊乱疾病的关系,以及精神紊乱病人疗效的监测。本文综述了近年来SERT显像剂的最新研究进展,并指出了今后该类显像剂的发展趋势。     

~（18）F标记放射性药物的新方法与新技术

PET显像技术具有高分辨率和高灵敏度。这一技术需要合适的正电子核素标记的药物。在一系列核素中1,8F是最适用于PET显像的。但是,氟的化学性质限制了18F药物的合成策略,大部分药物的18F标记费时费力。本文介绍了近几年18F标记放射性药物的新方法与新技术,包括18F脱标识法1、8F-FDG直接标记多肽、Al 18F络合...     

囊泡表面分子间通讯交流体系的构建: 利用受体的分子识别行为调控酶的活性

在人工双层膜囊泡表面, 构建了一个通过人工受体的分子识别行为控制酶反应活性的超分子体系. 体系以生物体细胞信号转导系统为模拟原型, 由作为受体的烷基胺、被受体识别的信号分子吡哆醛衍生物、乳酸脱氢酶、受体和酶之间的媒介物Cu^2＋以及作为体系载体的合成肽脂囊泡五个成分构成．通过UV-vis光谱法及动态光散射测定对体系进行了评价, 结果表明: 随着受体疏水参数增大, 其对信号分子的识别能力增强, 二者呈良好的线性关系; 通过信号分子与囊泡表面静电相互作用的研究表明信号分子具有选择性; 媒介物与信号分子–受体可形成化学计量比为1∶2的配合物, 其形成能力比媒介物与酶的结合能力更强．作为结论, 体系中烷基胺受体对磷酸吡哆醛信号分子的识别有效控制了处于囊泡表面的乳酸脱氢酶的活性．     

Al3+离子对卵磷脂聚集体结构的影响

本文用浊度滴定(UV-Vis)、透射电镜(TEM)和激光光散射(QELS)等方法对Al³⁺离子与卵磷脂(EYPC)囊泡之间的相互作用及其这种相互作用对溶液中磷脂微结构的影响进行了研究。结果表明，一定量的Al³⁺离子使EYPC多层囊泡转变为线团状聚集体;Al³⁺与牛磺胆酸钠(TC)的协同作用可以破坏EYPC的多层囊泡结构，促进相转变，形成混合胶束。     

Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans

Hallucinogens are a loosely defined group of compounds including LSD, N,N-dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), which can evoke intense visual and emotional experiences. We are witnessing a renaissance of research interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or single photon emission computer tomography (SPECT). In general, molecular imaging can depict the uptake and binding distribution of labelled hallucinogenic compounds or their congeners in the brain, as was shown in an early PET study with N¹-([¹¹C]-methyl)-2-bromo-LSD ([¹¹C]-MBL); displacement with the non-radioactive competitor ketanserin confirmed that the majority of [¹¹C]-MBL specific binding was to serotonin 5-HT_2A receptors. However, interactions at serotonin 5HT_1A and other classes of receptors and pleotropic effects on second messenger pathways may contribute to the particular experiential phenomenologies of LSD and other hallucinogenic compounds. Other salient aspects of hallucinogen action include permeability to the blood–brain barrier, the rates of metabolism and elimination, and the formation of active metabolites. Despite the maturation of radiochemistry and molecular imaging in recent years, there has been only a handful of PET or SPECT studies of radiolabeled hallucinogens, most recently using the 5-HT_2A/2C agonist N-(2[¹¹CH₃O]-methoxybenzyl)-2,5-dimethoxy- 4-bromophenethylamine ([¹¹C]Cimbi-36). In addition to PET studies of target engagement at neuroreceptors and transporters, there is a small number of studies on the effects of hallucinogenic compounds on cerebral perfusion ([¹⁵O]-water) or metabolism ([¹⁸F]-fluorodeoxyglucose/FDG). There remains considerable scope for basic imaging research on the sites of interaction of hallucinogens and their cerebrometabolic effects; we expect that hybrid imaging with PET in conjunction with functional magnetic resonance imaging (fMRI) should provide especially useful for the next phase of this research.     

The synthesis of a new cardiac sympathetic nerve imaging agent N-[11C]CH3-dopamine and biodistribution study

In this study, we synthesized and characterized N-[¹¹C]methyl-dopamine ([¹¹C]MDA) for cardiac sympathetic nerve imaging. [¹¹C]MDA was synthesized by direct N-methylation of dopamine with [¹¹C]methyl iodide and purified by semi-preparation reverse high pressure liquid chromatography (HPLC). The total synthesis time was 45 min including HPLC purification. The radiochemical yields of [¹¹C]MDA was 20 ± 3 %, without decay correction. The radiochemical purity was >98 % and the specific activity was about 50 GBq/mmol. The biological properties of [¹¹C]MDA were evaluated by biodistribution study in normal mice. PET imaging was performed in healthy Chinese mini-swines. Biodistribution study showed that [¹¹C]MDA had high myocardium uptake. PET/CT imaging showed [¹¹C]MDA had clear and symmetrical myocardium uptake, which was blocked obviously by injecting imipramine hydrochloride. [¹¹C]MDA would be a promising candidate of radiotracer for cardiac sympathetic nervous system imaging.     

Chemistry for Positron Emission Tomography: Recent Advances in 11C‐, 18F‐, 13N‐, and 15O‐Labeling Reactions

Positron emission tomography (PET) is a molecular imaging technology that provides quantitative information about function and metabolism in biological processes in vivo for disease diagnosis and therapy assessment. The broad application and rapid advances of PET has led to an increased demand for new radiochemical methods to synthesize highly specific molecules bearing positron‐emitting radionuclides. This Review provides an overview of commonly used labeling reactions through examples of clinically relevant PET tracers and highlights the most recent developments and breakthroughs over the past decade, with a focus on ¹¹C, ¹⁸F, ¹³N, and ¹⁵O.     

Synthesis of the dopamine D2/D3 receptor agonist (+)-PHNO via supercritical fluid chromatography: preliminary PET imaging study with [3-C]-(+)PHNO

Carbon-11 labeled (+)-4-[1-¹¹C]propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([1-¹¹C]-(+)-PHNO) is a dopamine D₃-preferring agonist radiopharmaceutical used for medical imaging by positron emission tomography (PET). We report the synthesis of (+)-PHNO using supercritical fluid chromatography for enantiomeric resolution of its norpropyl derivative, HNO, followed by propylation. (+)-HNO was used to prepare the radiolabeling precursor, (+)-trans-4-acetyl-9-triisopropylsilyloxy-2,3,4a,5,6,10b-hexahydro-4H-naphth[1,2b][1,4]oxazine, in 12 steps. Modifications to the labeling procedure were made to ensure consistent preparation of [3-¹¹C]-(+)-PHNO via [¹¹C]CH₃I. A preliminary PET imaging study was carried out with this tracer in an attempt to image dopamine receptors in brown adipose tissue (brown fat) in vivo.     

18F-labeling techniques for positron emission tomography

Much research effort has been made to understand various biological processes at levels of molecules using molecular imaging techniques.Because of great sensitivity,high resolution,and rapid detection,positron emission tomography(PET)imaging is becoming one of the most used imaging techniques for medical diagnose and pre-clinical studies.Here we provide a review on molecular imaging and PET imaging.An introduction is also provided on18F-fluorine labeling techniques for the preparation of PET imaging probes.A summary and comparison of currently available18F-fluorine labeling methods is provided.The perspectives for18F-fluorine labeling techniques are also given.     

Aluminum fluoride-18-labelled indocyanine green as a potential PET imaging agent for hepatic function reserve

Journal of Radioanalytical and Nuclear Chemistry - This study evaluated the potential of Al18F-labelled restrained complexing agent (RESCA)-ICG to assess hepatic function reserve on PET/CT imaging....     

An Improved Synthesis of N-(4-[18F]Fluorobenzoyl)-Interleukin-2 for the Preclinical PET Imaging of Tumour-Infiltrating T-cells in CT26 and MC38 Colon Cancer Models

Positron emission tomography (PET) imaging of activated T-cells with N-(4-[¹⁸F]fluorobenzoyl)-interleukin-2 ([¹⁸F]FB-IL-2) may be a promising tool for patient management to aid in the assessment of clinical responses to immune therapeutics. Unfortunately, existing radiosynthetic methods are very low yielding due to complex and time-consuming chemical processes. Herein, we report an improved method for the synthesis of [¹⁸F]FB-IL-2, which reduces synthesis time and improves radiochemical yield. With this optimized approach, [¹⁸F]FB-IL-2 was prepared with a non-decay-corrected radiochemical yield of 3.8 ± 0.7% from [¹⁸F]fluoride, 3.8 times higher than previously reported methods. In vitro experiments showed that the radiotracer was stable with good radiochemical purity (>95%), confirmed its identity and showed preferential binding to activated mouse peripheral blood mononuclear cells. Dynamic PET imaging and ex vivo biodistribution studies in naïve Balb/c mice showed organ distribution and kinetics comparable to earlier published data on [¹⁸F]FB-IL-2. Significant improvements in the radiochemical manufacture of [¹⁸F]FB-IL-2 facilitates access to this promising PET imaging radiopharmaceutical, which may, in turn, provide useful insights into different tumour phenotypes and a greater understanding of the cellular nature and differential immune microenvironments that are critical to understand and develop new treatments for cancers.     

Broad Scope and High-Yield Access to Unsymmetrical Acyclic [11C]Ureas for Biomedical Imaging from [11C]Carbonyl Difluoride

Effective methods are needed for labelling acyclic ureas with carbon-11 (t_1/2=20.4 min) as potential radiotracers for biomedical imaging with positron emission tomography (PET). Herein, we describe the rapid and high-yield syntheses of unsymmetrical acyclic [¹¹C]ureas under mild conditions (room temperature and within 7 min) using no-carrier-added [¹¹C]carbonyl difluoride with aliphatic and aryl amines. This methodology is compatible with diverse functionality (e. g., hydroxy, carboxyl, amino, amido, or pyridyl) in the substrate amines. The labelling process proceeds through putative [¹¹C]carbamoyl fluorides and for primary amines through isolable [¹¹C]isocyanate intermediates. Unsymmetrical [¹¹C]ureas are produced with negligible amounts of unwanted symmetrical [¹¹C]urea byproducts. Moreover, the overall labelling method tolerates trace water and the generally moderate to excellent yields show good reproducibility. [¹¹C]Carbonyl difluoride shows exceptional promise for application to the synthesis of acyclic [¹¹C]ureas as new radiotracers for biomedical imaging with PET.     

Pd0‐Mediated Rapid Cross‐Coupling Reactions,the Rapid C‐[11C]Methylations,Revolutionarily Advancing the Syntheses of Short‐Lived PET Molecular Probes

Positron emission tomography is a noninvasive method for monitoring drug (or diagnostic) behavior and its localization on the target molecules in the living systems, including the human body, using a short‐lived positron‐emitting radionuclide. New methodologies for introducing representative short‐lived radionuclides, ¹¹C and ¹⁸F, into the carbon frameworks of biologically active organic compounds have been established by developing rapid C‐[¹¹C]methylations and C‐[¹⁸F]fluoromethylations using rapid Pd⁰‐mediated cross‐coupling reactions between [¹¹C]methyl iodide (sp³‐hybridized carbon) and an excess amount of organotributylstannane or organoboronic acid ester having sp²(phenyl, heteroaromatic, or alkenyl), sp(alkynyl), or sp³(benzyl and cinnamyl)‐hybridized carbons; and [¹⁸F]fluoromethyl halide (iodide or bromide) and an organoboronic acid ester, respectively. These rapid reactions provide a firm foundation for an efficient and general synthesis of short‐lived ¹¹C‐ or ¹⁸F‐labeled PET molecular probes to promote in vivo molecular imaging studies.