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。     

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。     

Rapid and efficient purification of positron emission tomography probes by hydrophilic interaction chromatography

A rapid and efficient preparative high-performance liquid chromatographic procedure was established to purify short-lived positron emission tomography radio-probes. This method is based on hydrophilic interaction chromatography utilizing a semi-preparative silica column (10 mm I.D.) and a high volatile organic mobile phase (>90% acetonitrile). In nine different radiopharmaceuticals studied, six compounds could be separated from the unlabeled precursor with good resolution and faster elution than its precursor. These characteristics enabled significant shortening of the separation and evaporation processes in the manufacture of short-lived radiopharmaceuticals. Several ¹¹C-radiopharmaceuticals could be prepared within one half-life of carbon-11 (20.4 min), including radiosynthesis, purification and formulation steps with sufficient radiochemical/chemical purity and high levels of radioactivity/specific radioactivity.     

Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography

Positron emission tomography (PET) is a powerful and rapidly developing area of molecular imaging that is used to study and visualize human physiology by the detection of positron-emitting radiopharmaceuticals. Information about metabolism, receptor/enzyme function, and biochemical mechanisms in living tissue can be obtained directly from PET experiments. Unlike magnetic resonance imaging (MRI) or computerized tomography (CT), which mainly provide detailed anatomical images, PET can measure chemical changes that occur before macroscopic anatomical signs of a disease are observed. PET is emerging as a revolutionary method for measuring body function and tailoring disease treatment in living subjects. The development of synthetic strategies for the synthesis of new positron-emitting molecules is, however, not trivial. This Review highlights key aspects of the synthesis of PET radiotracers with the short-lived positron-emitting radionuclides (11)C, (18)F, (15)O, and (13)N, with emphasis on the most recent strategies.     

Fluorine-18 and medical imaging: Radiopharmaceuticals for positron emission tomography

Fluorine presents among its radioactive isotopes fluorine-18, that decays with a 109 min half-life and a β⁺ emission, allowing external detection of the two coincident γ photons obtained after annihilation. Production techniques (medical cyclotron), radiochemical reactions for isotope incorporation in radiopharmaceuticals and development of specific detection cameras (positron emission tomographs) allowed development of a vast investigation field in medical imaging.Applications of PET in oncology ([¹⁸F]fluorodeoxyglucose, FDG) largely improved detection and management of cancers; tracer molecules labelled with fluorine-18 also allow fruitful researches in molecular imaging.     

Ab initio computational study of positron emission tomography ligands interacting with lipid molecule for the prediction of nonspecific binding

Nonspecific binding is a poorly understood biological phenomenon of relevance in the study of small molecules interactions in vivo and in drug development. Nonspecific binding is thought to be correlated in part to a molecule's lipophilicity, typically estimated by measuring (or calculating) octanol-water partition coefficient. This is, however, a gross simplification of a complex phenomenon. In this article, we present a computational method whose aim is to help identify positron emission tomography (PET) ligands with low nonspecific binding characteristics by investigating the molecular basis of ligand-membrane interaction. We considered a set consisting of 10 well-studied central nervous system PET radiotracers acting on a variety of molecular targets. Quantum mechanical calculations were used to estimate the strength of the interaction between each drug molecule and one phospholipid molecule commonly present in mammalian membranes. The results indicate a correlation between the computed drug-lipid interaction energy and the in vivo nonspecific distribution volume relative to the free tracer plasma concentration, calculated using standard compartmental modeling for the analysis of PET data. Significantly, the drugs whose interaction with the lipid molecule more favorably possessed, in general, a higher nonspecific binding value, whereas for the drugs taken in consideration in this study, the water-octanol partition coefficient, log P, did not show good predictive power of the nonspecific binding. This study also illustrates how ab initio chemical methods may offer meaningful and unbiased insights for the understanding of the underlying chemical mechanisms in biological systems.     

Microfluidic reactions using [11C]carbon monoxide solutions for the synthesis of a positron emission tomography radiotracer

Microfluidic technology has been used to perform [(11)C]carbonylation reactions using solutions containing [(11)C]CO in the form of the complex, copper(i)tris(3,5-dimethylpyrazolyl)borate-[(11)C]carbonyl (Cu(Tp*)[(11)C]CO). The synthesis of the model compound [(11)C]N-benzylbenzamide and the known tracer molecule [(11)C]trans-N-[5-(2-flurophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofurane-1(3H),1'-cyclohexane]-4'-carboxamide ([(11)C]MK-0233), a ligand for the neuropeptide Y Y5 receptor, have been performed using this technique. Following semi-preparative HPLC purification and reformulation, 1262 ± 113 MBq of [(11)C]MK-0233 was produced at the end of the synthesis with a specific activity of 100 ± 30 GBq μmol(-1) and a >99% radiochemical purity. This corresponds to a decay corrected radiochemical yield of 7.2 ± 0.7%. Using a 3 mL vial as the reaction vessel, and following semi-preparative HPLC purification and reformulation, 1255 ± 392 MBq of [(11)C]MK-0233 was produced at the end of the synthesis with a specific activity of 100 ± 15 GBq μmol(-1) and a >99% radiochemical purity. This corresponds to a decay corrected radiochemical yield of 7.1 ± 2.2%.     

A novel electrosynthetic system for anodic substitution reactions by using parallel laminar flow in a microflow reactor

We have developed a novel electrosynthetic system for anodic substitution reactions by using parallel laminar flow in a microflow reactor. This system enables nucleophilic reactions to overcome the restraint, such as the oxidation potential of nucleophiles and the stability of cationic intermediates, by the combined use of ionic liquids as reaction media and the parallel laminar flow in the microflow reactor. By using this novel electrosynthetic system, the anodic substitution reaction of carbamates, especially of cyclic carbamates, with allyltrimethylsilane were carried out to provide the corresponding products in moderate to good conversion yields in a single flow-through operation at ambient temperature (without the need for low-temperature conditions).     

用于正电子断层扫描成像的68Ga标记PM2.5模拟粒子的制备及其活体示踪

将黑色素纳米颗粒(melanin nanoparticle,MNP)经聚乙二醇(polyethylene glycol,PEG)修饰制备得到PEG-MNP,随后通过与放射性的⁶⁸Ga³⁺离子螯合,高标记产率地制备得到⁶⁸Ga-PEG-MNP,标记产物稳定性良好。进一步将⁶⁸Ga-PEG-MNP通过雾化方式制备得到⁶⁸Ga-PEG-MNP PM_2.5(particulate matter 2.5,size<2.5μm)模拟颗粒,其经雾化小鼠吸入体内后,通过正电子断层扫描(positron emission tomography,PET)成像对小鼠进行全身显影,结果可见雾化的⁶⁸Ga-PEG-MNP PM_2.5模拟颗粒可由气管向肺部双叶区域扩散,并滞留于肺。体内的PET成像结果与离体放射自显影结果高度一致。     

Cu(I)-catalyzed (11)C carboxylation of boronic acid esters: a rapid and convenient entry to (11)C-labeled carboxylic acids, esters, and amides

Rapid and direct: the carboxylation of boronic acid esters with (11)CO(2) provides [(11)C]carboxylic acids as a convenient entry into [(11)C]esters and [(11)C]amides. This conversion of boronates is tolerant to diverse functional groups (e.g., halo, nitro, or carbonyl).     

Rapid Aqueous Late‐Stage Radiolabelling of [GaF3(BnMe2‐tacn)] by 18F/19F Isotopic Exchange: Towards New PET Imaging Probes

A simple and rapid method for ¹⁸F radiolabelling of [GaF₃(BnMe₂‐tacn)] by ¹⁸F/¹⁹F isotopic exchange is described. The use of MeCN/H₂O or EtOH/H₂O (75:25) and aqueous [¹⁸F]F^? (up to 200 MBq) with heating (80 °C, 10 min) gave 66±4 % ¹⁸F incorporation at a concentration of 268 nm , and 37±5 % ¹⁸F incorporation at even lower concentration (27 nm ), without the need for a Lewis acid promoter. A solid‐phase extraction method was established to give [Ga¹⁸F¹⁹F₂(BnMe₂‐tacn)] in 99 % radiochemical purity in an EtOH/H₂O mixture.     

Carbonylation of nitrobenzene in methanol with palladium bidentate phosphane complexes: an unexpectedly complex network of catalytic reactions, centred around a Pd-imido intermediate

The reactivity of palladium complexes of bidentate diaryl phosphane ligands (P₂) was studied in the reaction of nitrobenzene with CO in methanol. Careful analysis of the reaction mixtures revealed that, besides the frequently reported reduction products of nitrobenzene [methyl phenyl carbamate (MPC), N,N′‐diphenylurea (DPU), aniline, azobenzene (Azo) and azoxybenzene (Azoxy)], large quantities of oxidation products of methanol were co‐produced (dimethyl carbonate (DMC), dimethyl oxalate (DMO), methyl formate (MF), H₂O, and CO). From these observations, it is concluded that several catalytic processes operate simultaneously, and are coupled via common catalytic intermediates. Starting from a P₂Pd⁰ compound formed in situ, oxidation to a palladium imido compound P₂Pd^II?NPh, can be achieved by de‐oxygenation of nitrobenzene 1) with two molecules of CO, 2) with two molecules of CO and the acidic protons of two methanol molecules, or 3) with all four hydrogen atoms of one methanol molecule. Reduction of P₂Pd^II?NPh to P₂Pd⁰ makes the overall process catalytic, while at the same time forming Azo(xy), MPC, DPU and aniline. It is proposed that the Pd–imido species is the central key intermediate that can link together all reduction products of nitrobenzene and all oxidation products of methanol in one unified mechanistic scheme. The relative occurrence of the various catalytic processes is shown to be dependent on the characteristics of the catalysts, as imposed by the ligand structure.     

New approaches in radical carbonylation chemistry: fluorous applications and designed tandem processes by species-hybridization with anions and transition metal species

New approaches in radical carbonylation chemistry are described. We have successfully integrated tin mediated radical carbonylation chemistry into modern fluorous applications and separation techniques. We revealed that radical carbonylation reactions can be performed using fluorous tin mediators, such as fluorous tin hydride and fluorous allyltin reagents. Fine tuning of the reaction conditions resulted in a good efficiency equivalent to conventional tin mediators. The tedious procedure of removing organotin byproducts can be circumvented through the use of fluorous/organic liquid-liquid extraction or fluorous liquid-solid phase extraction with fluorous reverse phase silica (FRPS). Also described are newly developed tandem carbonylation reactions that are based on species hybridization approaches. Using a radical/anionic hybrid system based on zinc-induced one-electron reduction, we achieved a three-component coupling reaction consisting of 4-alkenyl iodides, carbon monoxide, and electron-deficient alkenes. We observed two types of annulations processes, namely [4 + 1](radical)/[3 + 2](anionic) and [5 + 1](radical)/[3 + 2](anionic), which lead to the production of bicyclo[3.3.0]octanols and bicyclo[3.2.1]octanols, respectively. We found a radical/palladium hybrid system to be useful in the construction of new cyclic systems that incorporate two or three molecules of carbon monoxide.     

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.     

General Method for the 11C‐Labeling of 2‐Arylpropionic Acids and Their Esters: Construction of a PET Tracer Library for a Study of Biological Events Involved in COXs Expression

Cyclooxygenase (COX) is a critical enzyme in prostaglandin biosynthesis that modulates a wide range of biological functions, such as pain, fever, and so on. To perform in vivo COX imaging by positron emission tomography (PET), we developed a method to incorporate ¹¹C radionuclide into various 2‐arylpropionic acids that have a common methylated structure, particularly among nonsteroidal anti‐inflammatory drugs (NSAIDs). Thus, we developed a novel ¹¹C‐radiolabeling methodology based on rapid C‐[¹¹C]methylation by the reaction of [¹¹C]CH₃I with enolate intermediates generated from the corresponding esters under basic conditions. One‐pot hydrolysis of the above [¹¹C]methylation products also allows the synthesis of desired ¹¹C‐incorporated acids. We demonstrated the utility of this method in the syntheses of six PET tracers, [¹¹C]Ibuprofen, [¹¹C]Naproxen, [¹¹C]Flurbiprofen, [¹¹C]Fenoprofen, [¹¹C]Ketoprofen, and [¹¹C]Loxoprofen. Notably, we found that their methyl esters were particularly useful as proradiotracers for a study of neuroinflammation. The microPET studies of rats with lipopolysaccharide (LPS)‐induced brain inflammation clearly showed that the radioactivity of PET tracers accumulated in the inflamed region. Among these PET tracers, the specificity of [¹¹C]Ketoprofen methyl ester was demonstrated by a blocking study. Metabolite analysis in the rat brain revealed that the methyl esters were initially taken up in the brain and then underwent hydrolysis to form pharmacologically active forms of the corresponding acids. Thus, we succeeded in general ¹¹C‐labeling of 2‐arylpropionic acids and their methyl esters as PET tracers of NSAIDs to construct a potentially useful PET tracer library for in vivo imaging of inflammation involved in COXs expression.