除FDG以外的用于肿瘤PET显像的^18F标记物

综述了除FDG以外的用于肿瘤PET显像的^18F标记物的研究和应用。这些^18F标记物主要包括：与相应受体结合的^18F标记的蛋白质和多肽，^18F标记的乏氧显像剂，用于评价基因治疗的^18F标记物等。此外，还介绍了用于诊断不同恶性肿瘤的^18F标记的组织特异性PET显像剂。     

多巴胺转运体显像剂^11C—CFT和^18F-CFT及其临床应用进展

使用^11C和^18F标记的托烷类衍生物的正电子显像剂是目前临床常规使用的正电子显像剂,^11C标记的显像剂^11C-2β-碳甲氧基-3β-（4-氟苯基）托烷（^11C—CFT）具有合成方法简单、比活度高、成本低等优点,但是^11C半衰期太短而限制了其临床使用;^18F—CFT具有半衰期长、临床使用方便而受到重视。^11C—CFT和^18F—CFT PET均被用于临床早期诊断帕金森病和对药物治疗疗效的监测。     

PET药物及其研究现状与进展

PET的发展离不开放射性药物,PET所采用的放射性药物是用"有机的"正电子发射体11C、13N、15O及18F(类氢)等标记的药物,目前已被研究与开发的有代谢型显像剂、结合型显像剂及血流和血容量显像剂等类型,用低原子序数或更高原子序数正电子发射体标记大分子物质的研究亦获得了成功。     

多巴胺转运体显像剂~(11)C-CFT和~(18)F-CFT及其临床应用进展

使用~(11)C和~(18)F标记的托烷类衍生物的正电子显像剂是目前临床常规使用的正电子显像剂,~(11)C标记的显像剂~(11)C-2β-碳甲氧基-3β-(4-氟苯基)托烷(~(11)C-CFT)具有合成方法简单、比活度高、成本低等优点,但是~(11)C半衰期太短而限制了其临床使用;~(18)F-CFT具有半衰期长、临床使用方便而受到重视.~(11)C-CFT和~(11)F-CFT PET均被用于临床早期诊断帕金森病和对药物治疗疗效的监测.     

2- 18F-氟丁酸作为PET/CT显像剂可行性的初步研究

目的:设计合成 18F标记的新型短链脂肪酸代谢型显像剂2- 18F-氟丁酸（2- 18F-FBA）,对其作为肿瘤PET/CT显像剂进行初步研究。 方法:前体2-溴丁酸甲酯通过 18F-亲核取代反应实现放射性标记,中间体2- 18F-氟丁酸甲酯经高效液...     

分子探针助于解决心血管显像尚未满足的临床需求(第1部分)：技术要点、心肌灌注和心脏神经显像

新型PET和SPECT显像剂的研发主要针对于未能满足的临床诊断需求, 这一需求体现了心血管医学中与分子表征和个性化治疗相关的全系统趋势。该文将分2部分讨论一些新型的放射性显像剂, 其可能有助于解决心血管医学核心领域中尚未解决的诊断方面的需求, 如心力衰竭、心律失常、瓣膜病、动脉粥样硬化和血栓。该文第1部分回顾了与心血管放射性显像剂研发相关的关键技术要点, 并综述了用于心肌灌注显像和心脏神经显像的新型放射性显像剂, 重点讨论了包括新型PET心肌灌注显像剂2-叔丁基-4-氯-5-[4-(2-氟-18F-乙氧基甲基)苯基甲氧基]-3(2H)-哒嗪酮(18F-flurpiridaz)、18F标记心脏神经显像剂(如18F-氟溴苯胍)等的研发;第2部分主要讨论了包括用于炎性反应、纤维化、血栓形成、钙化和心脏淀粉样变显像等的新型放射性显像剂。     

医用回旋加速器及正电子核素生产

PET(正电子发射体层)显像是利用解剖形态方式对体内各种生物化学过程如代谢和受体功能改变等进行评价和定量观测的核医学技术,PET的发展在一定程度上取决于正电子显像剂的研制与应用。PET所采用的正电子显像剂主要是用由回旋加速器生产的正电子核素-11C、13N、15I、18F等标记。因此,了解并掌握医用回旋加速器的基本组成和工作原理,选择适当的正电子核素及其标记前体,对正电子显像剂的常规生产和研究开发有重要的指导意义。主要介绍了回旋加速器的操作原理、医用回旋加速器的类型和正电子核素及其标记前体的生产。     

医用回旋加速器及正电子核素生产

PET（正电子发射体层）显像是利用解剖形态方式对体内各种生物化学过程如代谢和受体功能改变等进行评价和定量观测的核医学技术，PET的发展在一定程度上取决于正电子显像剂的研制与应用。PET所采用的正电子显像剂主要是用由回旋加速器生产的正电子核素－^11C、^13N、^15O、^18F等标记。因此，了解并掌握医用回旋加速器的基本组成和工作原理，选择适当的正电子核素及其标记前体，对正电子显像剂的常规生产和研究开发有重要的指导意义。主要介绍了回旋加速器的操作原理、医用回旋加速器的类型和正电子核素及其标记前体的生产。     

肿瘤增殖显像剂3'-脱氧-3'-18F-氟代胸苷

18F-氟代脱氧葡萄糖(18F-FDG)是广泛用于肿瘤诊断的PET显像剂,由于所有细胞都利用葡萄糖,因此,18F-FDG不是特异的肿瘤显像剂.3'-脱氧-3'-18F-氟代胸苷(18F-FLT)克服了18F-FDG的局限性,并可以进行细胞增殖显像.对于肿瘤的PET研究,18F-FLT是理想的反映增殖特性的示踪剂,18F-FLT利用胸苷激酶催化的磷酸化作用来评价DNA复制过程,可以准确地评估肿瘤细胞DNA的合成和细胞增殖活性,可用于肿瘤的早期诊断及鉴别诊断、化疗和放疗的疗效监测,是很有希望和发展前途的PET显像剂.     

碳-11乙酸盐正电子断层显像临床应用

正电子断层显像（positron emission tomography,PET）作为一种影像检查方法其临床应用价值已经得到广泛的认可,PET显像过程中必须使用的正电子显像剂有很多种,目前全世界范围内临床常规应用的正电子显像剂是氟-18标记的脱氧葡萄糖（18↑F-FDG）,与18↑F-FDG同期进入美国药典的正电子显像剂还有碳-11乙酸盐（11↑C-Acetate,以下简称11↑C-AC）.20世纪80年代初英国皇家医学研究生院Allan教授等发现11↑C-AC PET显像（简称AC-PET）可以用于心脏疾病诊断和疗效观察,早期其应用范围主要集中在心脏方面,1995年美国密西根大学安娜堡分校的Shreve等发现肾透明细胞病灶在AC-PET上显示为＂热灶＂,因此认为其有可能用于肿瘤显像.虽然作为一种短半衰期（20min）的显像剂,11↑C-AC临床应用受到很大限制,但因其在肿瘤中的应用价值独特,目前世界上越来越多的有加速器的PET中心开始常规使用该显像剂,     

Preparation of F-18 labeled annexin V: a potential PET radiopharmaceutical for imaging cell death

The clinical response to antitumor therapy is measured using imaging, such as CT or MRI, 6-12 weeks following chemotherapy treatment. The images at that time reflect both tumor cell death and new growth. Therefore, the amount of tumor cell death caused by chemotherapy cannot be efficiently quantified with current imaging modalities. A quantitative measurement of tumor cell death immediately following chemotherapy is needed to help validate both new agents and to optimize administration of existing therapies. Annexin V is a 36kD protein that binds to exposed phosphatidylserine (PS) on dying cells. In order to synthesize a probe that can detect cell death in vivo, the positron emitter F-18 was conjugated to annexin V via the compound N- succinimidyl-4-[18F]fluorobenzoate, [18F]SFB. The decay corrected radiochemical yield of F-18 labeled annexin V from 18F fluoride was 17.6 +/- 5.6% (n = 4) in three hours. The stepwise radiochemical yield of the conjugation step with annexin V was as high as 70% when a protein concentration of 5 mg/ml was used. Cancer cells treated with the chemotherapeutic agent, etoposide, showed an 88% increase in the binding of F-18 labeled annexin V compared to untreated cells. We conclude that [18F] labeled annexin V can be readily prepared by the conjugation of annexin V with [18F]SFB and that the positron-emitting compound is biologically active in detecting apoptosis.     

Synthesis of [18F]fluoromethyl iodide, a synthetic precursor for fluoromethylation of radiopharmaceuticals.

[18F]fluoroiodomethane was labeled via nucleophilic substitution of diiodomethane with [18F]fluoride, and labeling conditions were optimized. The optimized labeling yield was 40 +/- 8% (decay-corrected). The synthesis and purification of [18F]fluoroiodomethane took 15 min. The reactions of [18F]fluoroiodomethane with amine, carboxylic acid, thiol and phenoxide groups produced fluoromethylated derivatives with various yields (12-95%). The results indicated that [18F]fluoroiodomethane is a valuable synthetic precursor for the introduction of an [18F]fluoromethyl group into radiopharmaceuticals.     

Recent progress in fluorine-18 labelled peptide radiopharmaceuticals

The application of biologically active peptides labelled with positron-emitting nuclides has emerged as a useful and interesting field in nuclear medicine. Small synthetic receptor-binding peptides are currently the preferred agents over proteins and antibodies for diagnostic imaging of various tumours. Due to the smaller size of peptides, both higher target-to-background ratios and rapid blood clearance can often be achieved with radiolabelled peptides. Hence, short-lived positron emission tomography (PET) isotopes are potential candidates for labelling peptides. Among a number of positron-emitting nuclides, fluorine-18 appears to be the best candidate for labelling bioactive peptides by virtue of its favourable physical and nuclear characteristics. The major disadvantage of labelling peptides with 18F is the laborious and time-consuming preparation of the 18F labelling agents. In recent years, various techniques have been developed which allow efficient labelling of peptides with 18F without affecting their receptor-binding properties. Moreover, the development of a variety of prosthetic groups has facilitated the efficient and site-specific labelling of peptides with 18F. The 18F-labelled peptides hold enormous clinical potential owing to their ability to quantitatively detect and characterise a wide variety of human diseases when using PET. Recently, a number of 18F-labelled bioactive peptides have shown great promise as diagnostic imaging agents. This review presents the recent developments in 18F-labelled biologically active peptides used in PET.     

Synthesis and biological evaluation of a fluorine-18-labeled nonsteroidal androgen receptor antagonist, N-(3-[18F]fluoro-4-nitronaphthyl)-cis-5-norbornene-endo-2,3-dicarboxylic imide

INTRODUCTION: Androgen receptor (AR), which is overexpressed in most prostate cancers, is the target of androgen ablation and antiandrogen therapies: it is also the target for the receptor-mediated imaging of AR-positive prostate cancer using radiolabeled ligands. Previous AR imaging agents were based on a steroidal core labeled with fluorine. To develop a novel class of nonsteroidal imaging agents, with binding and pharmacological characteristics that are more similar to those of clinically used AR antagonists, we synthesized N-(3-fluoro-4-nitronaphthyl)-cis-5-norbornene-endo-2,3-dicarboxylic imide (3-F-NNDI), an analog of recently reported AR antagonist ligands. METHODS: 3-F-NNDI was synthesized in six steps starting with 1-nitronaphthalene, with fluorine incorporation as the final step. The labeling of 3-F-NNDI with fluorine-18 was achieved through a novel, extremely mild, S(N)Ar displacement reaction of an o-nitro-activated arene trimethylammonium salt, and 3-[(18)F]F-NNDI was prepared in high specific activity. RESULTS AND DISCUSSION: 3-F-NNDI was found to have an AR-binding affinity similar to that of its parent compound. In vitro assays demonstrated high stability of the labeled compound under physiological conditions in buffer and in the blood. Androgen target tissue uptake in diethylstilbestrol-pretreated male rats, however, was minimal, probably because of extensive metabolic defluorination the radiolabeled ligand. CONCLUSIONS: This study is part of our first look at a novel class of nonsteroidal AR antagonists as positron emission tomography (PET) imaging agents that are alternatives to steroidal AR agonist-based imaging agents. Although 3-[(18)F]F-NNDI has significant affinity for AR, it showed limited promise as a PET imaging agent because of its poor target tissue distribution properties.     

Recent progress in fluorine-18 labelled peptide radiopharmaceuticals

The application of biologically active peptides labelled with positron-emitting nuclides has emerged as a useful and interesting field in nuclear medicine. Small synthetic receptor-binding peptides are currently the preferred agents over proteins and antibodies for diagnostic imaging of various tumours. Due to the smaller size of peptides, both higher target-to-background ratios and rapid blood clearance can often be achieved with radiolabelled peptides. Hence, short-lived positron emission tomography (PET) isotopes are potential candidates for labelling peptides. Among a number of positron-emitting nuclides, fluorine-18 appears to be the best candidate for labelling bioactive peptides by virtue of its favourable physical and nuclear characteristics. The major disadvantage of labelling peptides with ¹⁸F is the laborious and time-consuming preparation of the ¹⁸F labelling agents. In recent years, various techniques have been developed which allow efficient labelling of peptides with ¹⁸F without affecting their receptor-binding properties. Moreover, the development of a variety of prosthetic groups has facilitated the efficient and site-specific labelling of peptides with ¹⁸F. The ¹⁸F-labelled peptides hold enormous clinical potential owing to their ability to quantitatively detect and characterise a wide variety of human diseases when using PET. Recently, a number of ¹⁸F-labelled bioactive peptides have shown great promise as diagnostic imaging agents. This review presents the recent developments in ¹⁸F-labelled biologically active peptides used in PET.     

Semiautomated synthesis of a novel [18F] amine fluorocyanoborane for PET imaging studies. Radiosynthesis and in vivo characterization in rats.

A novel fluorine-18 labeled amine fluorocyanoborane derivative was synthesized from the bromo-derivative precursor in 22% radiochemical yield. The [18F] labeling was accomplished by a semiautomatic method that is based on the synthesis of Ag 18F from Ag2CO3 and H 18F in a platinum dish followed by sonication of the bromo-precursor with Ag 18F in dry benzene to produce [18F] labeled amine fluorocyanoborane which was used with no further purification. A total of 50 microCi of the [18F] labeled amine fluorocyanoborane was injected into normal, female Sprague-Dawley rats (250-300 g) via the tail vein and monitored by Positron emission tomography (PET)/CT to detect its biodistribution in the rat body. The images showed an uptake of this compound in the bones of rats.     

Radiosynthesis of 1-[F]fluoroethyl-L-tryptophan as a novel potential amino acid PET tracer

¹⁸F labeled natural amino acids have been introduced as promising tumor imaging agents. A novel [¹⁸F]fluoro amino acid analog 1-[¹⁸F]fluoroethyl-L-tryptophan (1-[¹⁸F]FETrp) was designed and synthesized by a two-pot three-step procedure, including the synthesis of 1-[¹⁸F]fluoro-2- (tosyloxy)ethane, the [¹⁸F]fluoroethylation of the precursor N-Boc-L-tryptophan ethyl ester and following the deprotection of the tert-butoxycarbonyl and ethyl ester protecting groups. 1-[¹⁸F]FETrp was resulted in 0.9±0.2% (n=5) radiochemical yields (no decay corrected) by HPLC purification, within a total synthesis time of 65 min. The radiochemical purity of 1-[¹⁸F]FETrp was 95-97%. The radiosynthetic method needs to be further optimized to get a satisfying radiochemical yield.     

Radiolysis of 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) and the role of ethanol and radioactive concentration

Radiolysis is the process by which radioactively labeled compounds degrade. Many positron emission tomography (PET) radiopharmaceuticals produced with high radioactive concentrations and specific activities exhibit low radiochemical purity because of radiolysis. Little data exist that describe the radiolytic decomposition of 2-[¹⁸F]fluoro-2-deoxy-d-glucose ([¹⁸F]FDG). The objective of our study was to profile the degradation of [¹⁸F]FDG at various radioactive concentrations by measuring radiochemical purity at different time intervals and to study the effects of ethanol, a well-known reductant stabilizer of [¹⁸F]FDG preparations.     

Fluorine-18-labeled monoclonal antibody fragments: a potential approach for combining radioimmunoscintigraphy and positron emission tomography.

Monoclonal antibody fragments labeled with 18F could be useful for PET if selective tumor uptake could be achieved within a few half-lives of this nuclide. To evaluate this possibility, the F(ab')2 fragment of Mel-14, an antibody reactive with gliomas and other tumors, was labeled by reaction with N-succinimidyl-4-[18F]fluorobenzoate. The in-vitro binding properties of 18F-labeled Mel-14 F(ab')2 were nearly identical to those observed when this F(ab')2 was labeled by reaction with N-succinimidyl-4-[125I]iodobenzoate (18F, affinity constant = (6.7 +/- 1.1) x 10(8) M-1; 125I, affinity constant = (8.8 +/- 0.6) x 10(8) M-1). The tissue distribution of the two labeled fragments was compared in paired-label studies performed in athymic mice with subcutaneous D-54 MG human glioma xenografts. Uptake of both nuclides in tumor was rapid with levels as high as 18.7% +/- 1.1% injected dose/g for 18F and 19.4% +/- 1.0% injected dose/g for 125I observed by 4 hr after injection. Tumor-to-normal tissue ratios for 18F-labeled Mel-14 F(ab')2 at 4 hr ranged between 0.8:1 for kidneys to 40:1 for brain. These results suggest that it may be feasible to use 18F-labeled antibody fragments for imaging tumors with PET.     

18F-labeled FECNT: a selective radioligand for PET imaging of brain dopamine transporters

Fluorine-18 labeled 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nort ropane (FECNT) was synthesized in the development of a dopamine transporter (DAT) imaging ligand for positron emission tomography (PET). The methods of radiolabeling and ligand synthesis of FECNT, and the results of the in vitro characterization and in vivo tissue distribution in rats and in vivo PET imaging in rhesus monkeys of [18F]FECNT are described. Fluorine-18 was introduced into 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nort ropane (4) by preparation of 1-[18F]fluoro-2-tosyloxyethane (2) followed by alkylation of 2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane (3) in 21% radiochemical yield (decay corrected to end of bombardment [EOB]). Competition binding in cells stably expressing the transfected human DAT serotonin transporter (SERT) and norepinephrine transporter (NET) labeled by [3H]WIN 35428, [3H]citalopram, and [3H]nisoxetine, respectively, indicated the following order of DAT affinity: GBR 12909 > CIT > 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(3-fluoropropyl) nortropane (FPCT) > FECNT. The affinity of FECNT for SERT and NET was 25- and 156-fold lower, respectively, than for DAT. Blocking studies were performed in rats with a series of transporter-specific agents and demonstrated that the brain uptake of [18F]FECNT was selective and specific for DAT-rich regions. PET brain imaging studies in monkeys demonstrated high [18F]FECNT uptake in the caudate and putamen that resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 10.5 at 60 min. [18F]FECNT uptake in the caudate/putamen peaked in less than 75 min and exhibited higher caudate- and putamen-to-cerebellum ratios at transient equilibrium than reported for 11C-WIN 35,428, [11C]CIT/RTI-55, or [18F]beta-CIT-FP. Analysis of monkey arterial plasma samples using high performance liquid chromatography determined that there was no detectable formation of lipophilic radiolabeled metabolites capable of entering the brain. In equilibrium displacement experiments with CIT in rhesus monkeys, radioactivity in the putamen was displaced with an average half-time of 10.2 min. These results indicate that [18F]FECNT is a radioligand that is superior to 11C-WIN 35,428, [11C]CIT/RTI-55, [18F]beta-CIT-FP, and [18F]FPCT for mapping brain DAT in humans using PET.