- Radiosynthesis and preliminary evaluation of an 18F-labeled tubastatin A analog for PET imaging of histone deacetylase 6
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Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family because of its characteristics, namely, its cytoplasmic localization and ubiquitin binding. HDAC6 has been implicated in cancer metastasis and neurodegeneration. In the present study, we performed radiosynthesis and biological evaluation of a fluorine-18–labeled ligand [18F]3, which is an analog of the HDAC6-selective inhibitor tubastatin A, for positron emission tomography (PET) imaging. [18F]3 was synthesized by a two-step reaction composed of 18F-fluorination and formation of a hydroxamic acid group. IC50 values of 3 against HDAC1 and HDAC6 activities were 996 nM and 33.1 nM, respectively. A biodistribution study in mice demonstrated low brain uptake of [18F]3. Furthermore, bone radioactivity was stable at around 2% ID/g after injection, suggesting high tolerance to defluorination. Regarding metabolic stability, 70% of the compound was observed as the unchanged form at 30 minutes post injection in mouse plasma. A small animal PET study in mice showed that pretreatment with cyclosporine A had no effect on initial brain uptake of [18F]3, suggesting low brain uptake of [18F]3 was not caused by the P-glycoprotein–mediated efflux. While PET imaging using [18F]3 has a limitation with respect to neurodegenerative diseases, further studies evaluating its utility for certain cancers are worth evaluating.
- Ishii, Kenji,Tago, Tetsuro,Toyohara, Jun
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Read Online
- 18F-Radiolabeling and Preliminary Evaluation of a HSP90 ligand
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Purpose: With the ambition of improving the management of pancreatic neuroendocrine tumors (P-NETs), we developed and preliminary validated a novel fluorine-18 labelled HSP90 ligand. Methods: A precursor containing methoxymethyl ethers protecti
- Nordeman,Jayendra,Briard,Li,Larhed,Antoni,Estrada,Selvaraju,?berg,Jensen,St?lberg,Skogseid,Monazzam
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Read Online
- An unusual substitution reaction directed by an intramolecular re-arrangement
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Secondary amines and thiols undertake a substitution reaction on the side chain of 2-bromoethyl-pyridinium derivatives 'directed' by an intramolecular re-arrangement. Experimental investigations strongly indicate that the reaction is initiated by an alpha
- Parenty, Alexis D.C.,Smith, Louise V.,Cronin, Leroy
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Read Online
- Fluorine-18 click radiosynthesis and microPET/CT evaluation of a small peptide-a potential PET probe for carbonic anhydrase IX
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Carbonic anhydrase IX (CA IX) is the first carbonic anhydrase found to be associated with cancer that is over-expressed in a variety of human solid tumors. As a surrogate marker for hypoxia, the expression of CA IX is strongly upregulated in hypoxic tumor
- Jia, Lina,Li, Xiao,Cheng, Dengfeng,Zhang, Lan
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Read Online
- Radiosynthesis of [18F]DPA-714, a selective radioligand for imaging the translocator protein (18 kDa) with PET
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Recently, a novel series of 2-phenylpyrazolo[1,5-α] pyrimidineacetamides has been reported as selective ligands of the translocator protein (18 kDa). Within this series, DPA-714 (N,N-diethyl-2-(2-(4-(2- fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-α]pyri
- Damont, Annelaure,Hinnen, Francoise,Kuhnast, Bertrand,Schoellhorn-Peyronneau, Marie-Anne,James, Michelle,Luus, Christopher,Tavitian, Bertrand,Kassiou, Michael,Dolle, Frederic
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Read Online
- Fluoroalkyl azides for rapid radiolabeling and (Re)investigation of their potential towards: In vivo click chemistry
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In recent years, radiofluorinated alkyl azides have been reported for click radiolabeling and pretargeted PET imaging, but only little is known about the biodistribution and metabolism of these compounds. In this work, we present a significantly improved procedure for the synthesis of [18F]fluoroethyl azide and reinvestigated this radiolabeled probe in detail showing poor stability and very restricted suitability for in vivo application. Therefore, modified low-molecular-weight [18F]fluoroalkyl azides were developed. Propargyl-tagged endomorphin-1 (as model compound) was successfully radiolabeled in high yield and short reaction time making these probes useful and efficient bioorthogonal tools for rapid radiolabeling. Biodistribution, pharmacokinetics and in vivo stability were studied by preclinical PET/MR scanning and metabolite analysis. The results of this study revealed only limited applicability of [18F]fluoroalkyl azides for in vivo application.
- Denk, Christoph,Wilkovitsch, Martin,Skrinjar, Philipp,Svatunek, Dennis,Mairinger, Severin,Kuntner, Claudia,Filip, Thomas,Fr?hlich, Johannes,Wanek, Thomas,Mikula, Hannes
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Read Online
- Development of Novel 18F-PET Agents for Tumor Hypoxia Imaging
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Tumor hypoxia is a major factor responsible for tumor progression, metastasis, invasion, and treatment resistance, leading to low local tumor control and recurrence after radiotherapy in cancers. Here,18F-positron emission tomography (PET) probes are developed for visualizing viable hypoxic cells in biopsies. Pimonidazole derivatives and nitroimidazole-based agents bearing sulfonyl linkers were evaluated. A small-animal PET study showed that the tumor uptake of [18F]-23 [poly(ethylene glycols) (PEG)-sulfonyl linker] of 3.36 ± 0.29%ID/g was significantly higher (P 0.01) than that of [18F]-20 (piperazine-linker tracer, 2.55 ± 0.49%ID/g) at 2 h postinjection in UPPL tumors. The tumor-to-muscle uptake ratio of [18F]-23 (2.46 ± 0.48 at 2 h pi) was well improved compared with that of [18F]-FMISO (1.25 ± 0.14 at 2 h pi). A comparable distribution pattern was observed between ex vivo autoradiography of [18F]-23 and pimonidazole staining of the neighboring slice, indicating that [18F]-23 is a promising PET agent for hypoxia imaging.
- Wang, Li,Wang, Hui,Shen, Kun,Park, Hyejin,Zhang, Tao,Wu, Xuedan,Hu, Mei,Yuan, Hong,Chen, Yue,Wu, Zhanhong,Wang, Qiu,Li, Zibo
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p. 5593 - 5602
(2021/05/31)
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- Synthesis and biological evaluation of PET tracers designed for imaging of calcium activated potassium channel 3.1 (KCa3.1) channels: In vivo
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Expression of the Ca2+ activated potassium channel 3.1 (KCa3.1) channel (also known as the Gàrdos channel) is dysregulated in many tumor entities and has predictive power with respect to patient survival. Therefore, a positron emission tomography (PET) tracer targeting this ion channel could serve as a potential diagnostic tool by imaging the KCa3.1 channel in vivo. It was envisaged to synthesize [18F]senicapoc ([18F]1) since senicapoc (1) shows high affinity and excellent selectivity towards the KCa3.1 channels. Because problems occurred during 18F-fluorination, the [18F]fluoroethoxy senicapoc derivative [18F]28 was synthesized to generate an alternative PET tracer targeting the KCa3.1 channel. Inhibition of the KCa3.1 channel by 28 was confirmed by patch clamp experiments. In vitro stability in mouse and human serum was shown for 28. Furthermore, biodistribution experiments in wild type mice were performed. Since [18F]fluoride was detected in vivo after application of [18F]28, an in vitro metabolism study was conducted. A potential degradation route of fluoroethoxy derivatives in vivo was found which in general should be taken into account when designing new PET tracers for different targets with a [18F]fluoroethoxy moiety as well as when using the popular prosthetic group [18F]fluoroethyl tosylate for the alkylation of phenols.
- B?rgel, Frederik,Br?mmel, Kathrin,Budde, Thomas,Bulk, Etmar,Konken, Christian Paul,Obeng-Darko, Henry,Sch?fers, Michael,Schelhaas, Sonja,Schwab, Albrecht,Wünsch, Bernhard
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p. 30295 - 30304
(2021/10/25)
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- A novel18F-labeled clickable substrate for targeted imaging of SNAP-tag expressing cells by PETin vivo
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Bioorthogonal covalent labeling with self-labeling enzymes like SNAP-tag bears a high potential for specific targeting of cells for imagingin vitroand alsoin vivo. To this end, fluorescent SNAP substrates have been established and used in microscopy and fluorescence imaging while radioactive substrates for the highly sensitive and whole-body positron emission tomography (PET) have been lacking. Here, we show for the first time successful and high-contrast PET imaging of subcutaneous SNAP-tag expressing tumor xenografts by bioorthogonal covalent targeting with a novel18F-based radioligandin vivo.
- Depke, Dominic Alexej,Hermann, Sven,Konken, Christian Paul,Rentmeister, Andrea,R?sner, Lukas,Sch?fers, Michael
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supporting information
p. 9850 - 9853
(2021/10/08)
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- The landscape of the anti-kinase activity of the IDH1 inhibitors
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Isocitrate dehydrogenases constitute a class of enzymes that are crucial for cellular metabolism. The overexpression or mutation of isocitrate dehydrogenases are often found in leukemias, glioblastomas, lung cancers, and ductal pancreatic cancer among oth
- Malarz, Katarzyna,Mularski, Jacek,Musiol, Robert,Pacholczyk, Marcin
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- Novel derivatives of anaplastic lymphoma kinase inhibitors: Synthesis, radiolabeling, and preliminary biological studies of fluoroethyl analogues of crizotinib, alectinib, and ceritinib
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Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.
- Radaram, Bhasker,Pisaneschi, Federica,Rao, Yi,Yang, Ping,Piwnica-Worms, David,Alauddin, Mian M.
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- 18F-LABELED PEPTIDE LIGANDS USEFUL IN PET AND CERENKOV LUMINESCENE IMAGING
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The present technology is directed to compounds, intermediates thereof, compositions thereof, medicaments thereof, and methods related to the imaging of mammalian tissue via 18F- labeled peptide ligands disclosed herein.
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Paragraph 0115; 0116
(2019/07/13)
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- COMPOUNDS, SALTS THEREOF AND METHODS FOR TREATMENT OF DISEASES
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The present disclosure relates to compounds according to Formulae (I), (II) and (VIII), useful for treating diseases.
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Paragraph 00257; 00258
(2019/03/12)
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- Synthesis and preliminary evaluation of 18F-icotinib for EGFR-targeted PET imaging of lung cancer
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Epidermal growth factor receptor (EGFR) has emerged as an attracting target in the field of imaging and treatment for non-small cell lung cancer (NSCLC). Radiolabeled EGFR-tyrosine kinase inhibitors (EGFR-TKIs) specifically targeting EGFR are deemed as pr
- Lu, Xinmiao,Wang, Cheng,Li, Xiao,Gu, Peilin,Jia, Lina,Zhang, Lan
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p. 545 - 551
(2019/01/05)
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- Radiosynthesis of (R,S)-[18F]GE387: A Potential PET Radiotracer for Imaging Translocator Protein 18 kDa (TSPO) with Low Binding Sensitivity to the Human Gene Polymorphism rs6971
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Translocator protein (TSPO) is a biomarker of neuroinflammation, which is a hallmark of many neurodegenerative diseases and has been exploited as a positron emission tomography (PET) target. Carbon-11-labelled PK11195 remains the most applied agent for imaging TSPO, despite its short-lived isotope and low brain permeability. Second-generation radiotracers show variance in affinity amongst subjects (low-, mixed-, and high-affinity binders) caused by the genetic polymorphism (rs6971) of the TSPO gene. To overcome these limitations, a new structural scaffold was explored based on the TSPO pharmacophore, and the analogue with a low-affinity binder/high-affinity binder (LAB/HAB) ratio similar (1.2 vs. 1.3) to that of (R)-[11C]PK11195 was investigated. The synthesis of the reference compound was accomplished in six steps and 9 % overall yield, and the precursor was prepared in eight steps and 8 % overall yield. The chiral separation of the reference and precursor compounds was performed using supercritical fluid chromatography with >95 % ee. The absolute configuration was determined by circular dichroism. Optimisation of reaction conditions for manual radiolabelling revealed acetonitrile as a preferred solvent at 100 °C. Automation of this radiolabelling method provided R and S enantiomers in respective 21.3±16.7 and 25.6±7.1 % decay-corrected yields and molar activities of 55.8±35.6 and 63.5±39.5 GBq μmol?1 (n=3). Injection of the racemic analogue into a healthy rat confirmed passage through the blood–brain barrier.
- Qiao, Luxi,Fisher, Emily,McMurray, Lindsay,Milicevic Sephton, Selena,Hird, Matthew,Kuzhuppilly-Ramakrishnan, Nisha,Williamson, David J.,Zhou, Xiouyun,Werry, Eryn,Kassiou, Michael,Luthra, Saijinder,Trigg, William,Aigbirhio, Franklin I.
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p. 982 - 993
(2019/04/17)
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- Convenient Entry to 18F-Labeled Amines through the Staudinger Reduction
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Fluorine-18 possesses outstanding decay characteristics for positron emission tomography (PET) imaging. Therefore, it is ideally suited for clinical applications. As such, improved strategies to incorporate fluorine-18 into bioactive molecules are of utmo
- Stéen, E. Johanna L.,Shalgunov, Vladimir,Denk, Christoph,Mikula, Hannes,Kj?r, Andreas,Kristensen, Jesper L.,Herth, Matthias M.
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supporting information
p. 1722 - 1725
(2019/01/30)
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- PHOSPHONIUM COMPOUND AND PRODUCTION METHOD THEREFOR
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The present invention provides a phosphonium compound of formula (II). Also provided is a method for producing a quaternary phosphonium compound labeled with a positron emitting radionuclide, the method comprising the step of reacting an electrophile of f
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Paragraph 0188-0191
(2018/02/28)
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- Harnessing the Maltodextrin Transport Mechanism for Targeted Bacterial Imaging: Structural Requirements for Improved in vivo Stability in Tracer Design
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Diagnosis and localization of bacterial infections remains a significant clinical challenge. Harnessing bacteria-specific metabolic pathways, such as the maltodextrin transport mechanism, may allow specific localization and imaging of small or hidden colo
- Axer, Alexander,Hermann, Sven,Kehr, Gerald,Clases, David,Karst, Uwe,Fischer-Riepe, Lena,Roth, Johannes,Fobker, Manfred,Sch?fers, Michael,Gilmour, Ryan,Faust, Andreas
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supporting information
p. 241 - 250
(2018/01/22)
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- A 18F radiolabelled Zn(II) sensing fluorescent probe
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A selective fluorescent probe for Zn(ii), AQA-F, has been synthesized. AQA-F exhibits a ratiometric shift in emission of up to 80 nm upon binding Zn(ii) ([AQA-F] = 0.1 mM, [Zn(ii)Cl2] = 0-300 μM). An enhancement of quantum yield from Φ = 4.2% t
- Price, Thomas W.,Firth, George,Eling, Charlotte J.,Kinnon, Michelle,Long, Nicholas J.,Sturge, Justin,Stasiuk, Graeme J.
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supporting information
p. 3227 - 3230
(2018/04/05)
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- Radiosynthesis and biological evaluation of 18F-labeled 4-anilinoquinazoline derivative (18F-FEA-Erlotinib) as a potential EGFR PET agent
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Epidermal growth factor receptor (EGFR) has gained significant attention as a therapeutic target. Several EGFR targeting drugs (Gefitinib and Erlotinib) have been approved by US Food and Drug Administration (FDA) and have received high approval in clinica
- Huang, Shun,Han, Yanjiang,Chen, Min,Hu, Kongzhen,Qi, Yongshuai,Sun, Penghui,Wang, Men,Wu, Hubing,Li, Guiping,Wang, Quanshi,Du, Zhiyun,Zhang, Kun,Zhao, Suqing,Zheng, Xi
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supporting information
p. 1143 - 1148
(2018/03/01)
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- Synthesis and evaluation of antiplasmodial activity of 2,2,2-trifluoroethoxychalcones and 2-fluoroethoxy chalcones against plasmodium falciparum in culture
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A new class of compounds comprising two series of chalcones with 2,2,2-trifluoroethoxy group and 2-fluoroethoxy groups were synthesized and screened for in vitro antiplasmodial activity against Plasmodium falciparum (3D7) using the [3H] hypoxanthine incorporation inhibition assay. Chalcones with 2,2,2-trifluoroethoxy groups substituted on the p- and m-positions of the 1-phenyl ring showed weak antiplasmodial activity, while compounds substituted on the o-position of the 1-phenyl ring displayed enhanced antiplasmodial activity, thus indicating that 2,2,2-trifluoroethoxy groups on the 1-phenyl ring of chalcones show position-dependent antiplasmodial activity. Of the 34 compounds synthesized, chalcones 3a and 3f exhibited significant inhibitory effects, with IC50 values of 3.0 μg/mL and 2.2 μg/mL, respectively. Moreover, these compounds 3a and 3f showed profound antiplasmodial activity in combination with artemisinin in vitro. The most active molecules, 3a, and 3f, were further assessed for their cytotoxicity towards mammalian Vero cells and the selectivity index (SI) values are 8.6, and 8.2 respectively, being considered non-toxic. We also studied the antiplasmodial activity of 2-fluoroethoxychalcones to discern the effect of the number of fluorine atoms in the fluoroethoxy group. Our results showed that chalcones with 2-fluoroethoxy group on the 1-phenyl ring exhibited more enhanced inhibitory effects on the growth of parasites than their trifluoro analogues, which reveals that monofluoroethoxy group is generally more effective than trifluoroethoxy group in the inhibition of parasite growth. Thus o-2,2,2-trifluoroethoxychalcones (Series 3) and 2-fluoroethoxychalcones may serve as good antiplasmodial candidates for future further development.
- Devi, Kavita,Rajendran, Vinoth,Ayushee,Rangarajan,Singh, Rishi Pal,Ghosh, Prahlad C.,Singh, Manjula
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- RADIOLABELED COMPOUNDS THAT TARGET ORGANIC CATION TRANSPORTERS AND USES THEREOF IN RADIOIMAGING
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Radiolabeled quaternary ammonium salt compounds featuring a quinoline skeleton and uses thereof in radioimaging are provided. The radiolabeled compounds are usable for determining a presence and/or level and/or distribution of an organic cation transporte
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Page/Page column 52
(2018/12/03)
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- 18F-LABELED TRIAZOLE CONTAINING PSMA INHIBITORS
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The present technology is directed to compounds, intermediates thereof, compositions thereof, medicaments thereof, and methods related to the imaging of mammalian tissue overexpressing PSMA. The compounds are of Formula I or a pharmaceutically acceptable salt thereof, wherein one of R1, R2, and R3 is and of Formula IV or a pharmaceutically acceptable salt thereof.
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Paragraph 0109
(2018/02/03)
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- Synthesis and evaluation of novel F-18-labeled pyrimidine derivatives: Potential FAK inhibitors and PET imaging agents for cancer detection
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Based on computer-assisted drug design, a series of novel pyrimidine derivatives was successfully synthesized and characterized by 1H NMR, 13C HNMR, and MS spectra. All the new compounds were evaluated for their activity against focal adhesion kinase and showed low IC50 values in comparison with control drugs. In particular, for compound 8i, its IC50 value was 0.060 μM, suggesting its advantage as a focal adhesion kinase inhibitor. To evaluate the potentiality of these compounds as PET imaging agents in cancer detection, compounds 8a, 8c, 8h, and 8i were successively labeled with 18F. The four 18F-labeled pyrimidine derivatives showed appropriate log P values and high stability in physiological saline and mouse plasma. Noticeably, compound [18F]-8a with a 4-methoxyl group at the benzene ring exhibited good in vivo biodistribution data in mice bearing the S180 tumor, which promoted a further microPET imaging study of compound [18F]-8a. The microPET image of [18F-8a] administered into the S180 tumor-bearing mice acquired at 60 min post-injection illustrated that the uptake in S180 tumor was obvious. These results suggested that compound [18F]-8a might be a new probe for PET tumor imaging.
- Wang, Dawei,Fang, Yu,Wang, Hang,Xu, Xingyu,Liu, Jianping,Zhang, Huabei
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p. 22388 - 22399
(2017/07/10)
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- Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior
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Dopamine D3 receptor-mediated networks have been associated with a wide range of neuropsychiatric diseases, drug addiction and food maintained behavior, which makes D3 a highly promising biological target. The previously described do
- St??el, Anne,Brox, Regine,Purkayastha, Nirupam,Hübner, Harald,Hocke, Carsten,Prante, Olaf,Gmeiner, Peter
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supporting information
p. 3491 - 3499
(2017/05/29)
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- Selective targeting of melanoma using N-(2-diethylaminoethyl) 4-[18F]fluoroethoxy benzamide (4-[18F]FEBZA): a novel PET imaging probe
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Background: The purpose of this study was to develop a positron emission tomography (PET) imaging probe that is easy to synthesize and selectively targets melanoma in vivo. Herein, we report the synthesis and preclinical evaluation of N-(2-diethylaminoeth
- Garg, Pradeep K.,Nazih, Rachid,Wu, Yanjun,Grinevich, Vladimir P.,Garg, Sudha
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- Synthesis of a [18F]-labeled ceritinib analogue for positron emission tomography of anaplastic lymphoma kinase, a receptor tyrosine kinase, in lung cancer
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Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, has emerged as a therapeutic target in solid and hematologic tumors. Although several ALK inhibitors have gained recent approval for therapy, non-invasive indicators of target engagement or for use as predictive biomarkers in vivo are lacking. Therefore, we designed and synthesized a radiolabeled analogue of the ALK inhibitor ceritinib, [18F]fluoroethyl-ceritinib ([18F]-FEC), for use with positron emission tomography. We used two methods to synthesize [18F]-FEC. First, [18F]fluoroethyl-tosylate was prepared, coupled with ceritinib, and the product purified to yield [18F]-FEC. Alternatively, a precursor compound was synthesized, directly fluorinated with 18F-fluoride, and purified to yield [18F]-FEC. The first method produced [18F]-FEC with an average decay-corrected yield of 24% (n = 4), specific activity of 1200 mCi/μmol, and >99% purity; synthesis time was 115 min from the end of bombardment. The second method produced [18F]-FEC with an average yield of 7% (n = 4), specific activity of 1500 mCi/μmol, and >99% purity; synthesis time was 65 min from the end of bombardment. The synthesis of a novel 18F-labeled analogue of ceritinib has been achieved in acceptable yields, at high purity, and with high specific activity. The compound is a potential positron emission tomography imaging agent for the detection of ALK-overexpressing solid tumors such as lung cancer. Synthesis of [18F]-fluoroethyl-ceritinib for positron emission tomography is reported. Reaction of [18F]-fluoroethyl-tosylate with ceritinib produced the product in good yield, with high purity and specific activity. The compound is a potential positron emission tomography imaging agent for the detection of anaplastic lymphoma kinase-overexpressing solid tumors such as lung cancer.
- Perera, Sandun,Piwnica-Worms, David,Alauddin, Mian M.
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p. 103 - 108
(2016/03/12)
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- In vivo imaging method for cancer
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The present invention provides a method useful in the diagnosis and monitoring of cancer wherein there is an abnormal expression of PBR. The method of the invention is particularly useful in evaluating the severity of the cancer, e.g. PBR expression corre
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Page/Page column 26
(2016/05/11)
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- 11C- and 18F-Labeled Radioligands for P-Glycoprotein Imaging by Positron Emission Tomography
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P-Glycoprotein (P-gp) is an efflux transporter widely expressed at the human blood-brain barrier. It is involved in xenobiotics efflux and in onset and progression of neurodegenerative disorders. For these reasons, there is great interest in the assessmen
- Cantore, Mariangela,Benadiba, Marcel,Elsinga, Philip H.,Kwizera, Chantal,Dierckx, Rudi A. J. O.,Colabufo, Nicola Antonio,Luurtsema, Gert
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p. 108 - 118
(2016/01/15)
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- Synthesis, in Vitro Evaluation, and Radiolabeling of Fluorinated Puromycin Analogues: Potential Candidates for PET Imaging of Protein Synthesis
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There is currently no ideal radiotracer for imaging of protein synthesis rate (PSR) by positron emission tomography (PET). Existing fluorine-18-labeled amino acid-based radiotracers predominantly visualize amino acid transporter processes, and in many cases they are not incorporated into nascent proteins at all. Others are radiolabeled with the short-half-life positron emitter carbon-11, which is rather impractical for many PET centers. Based on the puromycin (6) structural manifold, a series of 10 novel derivatives of 6 was prepared via Williamson ether synthesis from a common intermediate. A bioluminescence assay was employed to study their inhibitory action on protein synthesis, which identified the fluoroethyl analogue 7b as a lead compound. The fluorine-18 analogue was prepared via nucleophilic substitution of the corresponding tosylate precursor in a modest radiochemical yield of 2 ± 0.6% with excellent radiochemical purity (>99%) and showed complete stability over 3 h at ambient temperature.
- Betts, Helen M.,Milicevic Sephton, Selena,Tong, Carmen,Awais, Ramla O.,Hill, Philip J.,Perkins, Alan C.,Aigbirhio, Franklin I.
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supporting information
p. 9422 - 9430
(2016/11/11)
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- On both sides of the high-state metastatis hyperlipidemia Antialdosterone and having one side for diagnosis of the state of the radioactive pharmaceutical PET
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A functional PET imaging method is disclosed for differentiation between bilateral hyperplasia and unilateral adenoma comprising (1) introducing a radioactively labelled CYP11 B2 (aldosterone synthase) inhibitor which binds selectively to CYP11 B2 (aldosterone synthase) relative to CYP11 B1 (112-hydroxylase) into a mammal with adrenal glands and (2) conducting positron emission tomography (PET) in the region of the adrenal glands to obtain a functional PET image of the adrenal glands. Also disclosed are radioactive tracer compounds suitable for use in this method, precursors for making the same, and a process for making the radioactive tracer compounds capable of being conducted as a rapid one-pot reaction.
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Paragraph 0042
(2017/02/09)
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- Novel fluoroalkyl derivatives of selective kappa opioid receptor antagonist JDTic: Design, synthesis, pharmacology and molecular modeling studies
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Novel N-and O-fluoroalkyl derivatives of the highly potent KOR antagonist JDTic were designed and synthesized. Their opioid receptor properties were compared in both in vitro binding assays and modeling approach. All compounds displayed nanomolar affiniti
- Schmitt, Sébastien,Colloc'H, Nathalie,Perrio, Cécile
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p. 742 - 750
(2015/04/14)
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- p27 PROTEIN INDUCER
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The present invention provides a p27 protein inducing agent comprising a compound represented by general formula (11) below or pharmaceutically acceptable salt thereof as an active ingredient: wherein G 1 , G 2 , G 3 and G 8 are each independently selected from -N= etc., Ring G 6 is selected from divalent aryl etc., A is selected from amino etc., G 4 is selected from oxygen etc., G 5 is selected from oxygen etc., G 7 is selected from -CH 2 - etc., and R 2 is selected from C 1-6 alkyl etc.
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Paragraph 0953-0956
(2016/10/08)
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- In vivo imaging method of mood disorders
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The present invention provides a method useful in the diagnosis and/or monitoring of mood disorders wherein there is an abnormal expression of PBR. The method of the invention is useful in the differential diagnosis of said mood disorders and other condit
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Page/Page column 25; 26
(2015/11/09)
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- N 1-fluoroalkyltryptophan analogues: Synthesis and in vitro study as potential substrates for indoleamine 2,3-dioxygenase
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Indoleamine 2,3-dioxygenase (hIDO) is an enzyme that catalyzes the oxidative cleavage of the indole ring of l-tryptophan through the kynurenine pathway, thereby exerting immunosuppressive properties in inflammatory and tumoral tissues. The syntheses of 1-(2-fluoroethyl)-tryptophan (1-FETrp) and 1-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methyl)-tryptophan, two N1-fluoroalkylated tryptophan derivatives, are described here. In vitro enzymatic assays with these two new potential substrates of hIDO show that 1-FETrp is a good and specific substrate of hIDO. Therefore, its radioactive isotopomer, 1-[18F]FETrp, should be a molecule of choice to visualize tumoral and inflammatory tissues and/or to validate new potential inhibitors.
- Henrottin, Jean,Zervosen, Astrid,Lemaire, Christian,Sapunaric, Frédéric,Laurent, Sophie,Van Den Eynde, Benoit,Goldman, Serge,Plenevaux, Alain,Luxen, André
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supporting information
p. 260 - 265
(2015/03/30)
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- Synthesis and Preclinical Evaluation of Three Novel Fluorine-18 Labeled Radiopharmaceuticals for P-Glycoprotein PET Imaging at the Blood-Brain Barrier
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P-Glycoprotein (P-gp), along with other transporter proteins at the blood-brain barrier (BBB), limits the entry of many pharmaceuticals into the brain. Altered P-gp function has been found in several neurological diseases. To study the P-gp function, many positron emission tomography (PET) radiopharmaceuticals have been developed. Most P-gp radiopharmaceuticals are labeled with carbon-11, while labeling with fluorine-18 would increase their applicability due to longer half-life. Here we present the synthesis and in vivo evaluation of three novel fluorine-18 labeled radiopharmaceuticals: 4-((6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-2-(4-fluorophenyl)oxazole (1a), 2-biphenyl-4-yl-2-fluoroethoxy-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (2), and 5-(1-(2-fluoroethoxy))-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen (3). Compounds were characterized as P-gp substrates in vitro, and Mdr1a/b(-/-)Bcrp1(-/-) and wild-type mice were used to assess the substrate potential in vivo. Comparison was made to (R)-[11C]verapamil, which is currently the most frequently used P-gp substrate. Compound [18F]3 was performing the best out of the new radiopharmaceuticals; it had 2-fold higher brain uptake in the Mdr1a/b(-/-)Bcrp1(-/-) mice compared to wild-type and was metabolically quite stable. In the plasma, 69% of the parent compound was intact after 45 min and 96% in the brain. Selectivity of [18F]3 to P-gp was tested by comparing the uptake in Mdr1a/b(-/-) mice to uptake in Mdr1a/b(-/-)Bcrp1(-/-) mice, which was statistically not significantly different. Hence, [18F]3 was found to be selective for P-gp and is a promising new radiopharmaceutical for P-gp PET imaging at the BBB. (Chemical Equation).
- Savolainen, Heli,Cantore, Mariangela,Colabufo, Nicola A.,Elsinga, Philip H.,Windhorst, Albert D.,Luurtsema, Gert
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p. 2265 - 2275
(2015/07/15)
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- 6,7-DIOXYALKYLTETRAHYDROISOQUINOLINE COMPOUNDS
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The present invention relates to a 6,7-dioxyalkyltetrahydroisoquinoline compound, or a salt or solvate thereof according to formula I: (formula I), (I) wherein R represents hydrogen or a fluorinated alkyl group, and R2 and R3 independently represents hydrogen or an alkyl group.
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Page/Page column 9
(2016/08/03)
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- New N-aryl-N′-(3-(substituted)phenyl)-N′-methylguanidines as leads to potential PET radioligands for imaging the open NMDA receptor
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An expansive set of N-aryl-N′-(3-(substituted)phenyl)-N′-methylguanidines was prepared in a search for new leads to prospective PET ligands for imaging of the open channel of the N-methyl-d-aspartate (NMDA) receptor in vivo. The N-aryl rings and their substituents were varied, whereas the N-methyl group was maintained as a site for potential labeling with the positron-emitter, carbon-11 (t1/2 = 20.4 min). At micromolar concentration, over half of the prepared compounds strongly inhibited the binding of [3H]TCP to its binding site in the open NMDA receptor in vitro. Four ligands displayed affinities that are similar or superior to those of the promising SPECT radioligand ([123I]CNS1261). The 3′-dimethylamino (19; Ki 36.7 nM), 3′-trifluoromethyl (20; Ki 18.3 nM) and 3′-methylthio (2; Ki 39.8 nM) derivatives of N-1-naphthyl-N′-(phenyl)-N′-methylguanidine were identified as especially attractive leads for PET radioligand development.
- Naumiec, Gregory R.,Cai, Lisheng,Pike, Victor W.
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supporting information
p. 225 - 228
(2015/03/03)
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- N′-3-(Trifluoromethyl)phenyl Derivatives of N-Aryl-N′-methylguanidines as Prospective PET Radioligands for the Open Channel of the N-Methyl- d -aspartate (NMDA) Receptor: Synthesis and Structure-Affinity Relationships
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N-Methyl-d-aspartate (NMDA) receptor dysfunction has been linked to several neuropsychiatric disorders, including Alzheimer's disease, epilepsy, drug addiction, and schizophrenia. A radioligand that could be used with PET to image and quantify human brain NMDA receptors in the activated "open channel" state would be useful for research on such disorders and for the development of novel therapies. To date, no radioligands have shown well-validated efficacy for imaging NMDA receptors in human subjects. In order to discover improved radioligands for PET imaging, we explored structure-affinity relationships in N′-3-(trifluoromethyl)phenyl derivatives of N-aryl-N′-methylguanidines, seeking high affinity and moderate lipophilicity, plus necessary amenability for labeling with a positron-emitter, either carbon-11 or fluorine-18. Among a diverse set of 80 prepared N′-3-(trifluoromethyl)phenyl derivatives, four of these compounds (13, 19, 20, and 36) displayed desirable low nanomolar affinity for inhibition of [3H](+)-MK801 at the PCP binding site and are of interest for candidate PET radioligand development.
- Naumiec, Gregory R.,Jenko, Kimberley J.,Zoghbi, Sami S.,Innis, Robert B.,Cai, Lisheng,Pike, Victor W.
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supporting information
p. 9722 - 9730
(2016/01/12)
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- The flocculated acryloyldimethyltauric molecule ligand
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Provided are certain benzothiazole, imidazothiazole, imidazopyrimidine and imidazopyridine compounds, including, for example: formula (I) and pharmaceutically and physiologically acceptable salts, hydrates, and solvates thereof. Such compounds can be used as diagnostic ligands or labels of tau protein and PHF.
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Paragraph 0705; 0706
(2016/10/08)
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- CYCLOPROPANECARBOXAMIDO-SUBSTITUTE AROMATIC COMPOUNDS AS ANTI-TUMOR AGENTS
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Provided are cyclopropanecarboxamido-substituted aromatic compounds that inhibit protein kinases and their use in anti-tumor area. In particular, tyrosine-kinase inhibitors and Raf-kinase inhibitors as anti-tumor agents, their preparation, pharmaceutical composition, and their use in the treatment of cancer are also provided.
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Paragraph 0268; 0269
(2015/07/22)
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- AROMATIC AMINO ACID DERIVATIVE AND POSITRON EMISSION TOPOGRAPHY (PET) PROBE UTILIZING SAME
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A compound having a structure represented by the general formula (I): (wherein n is 0 or 1; R1 represents a hydrogen atom (only if n = 0), a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, an optionally substituted amino group, an o
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Paragraph 0056
(2016/01/12)
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- Novel fluoroalkyl derivatives of selective kappa opioid receptor antagonist JDTic: Design, synthesis, pharmacology and molecular modeling studies
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Novel N- and O-fluoroalkyl derivatives of the highly potent KOR antagonist JDTic were designed and synthesized. Their opioid receptor properties were compared in both in vitro binding assays and modeling approach. All compounds displayed nanomolar affinit
- Schmitt, Sbastien,Colloc'h, Nathalie,Perrio, Ccile
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p. 742 - 750
(2015/02/19)
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- Mild copper-catalyzed fluorination of alkyl triflates with potassium fluoride
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A chemoselective catalytic fluorination of alkyl triflates is described using potassium fluoride as a fluoride source. Excellent yields of the desired alkyl fluorides are obtained after one hour at 45°C using 2 mol% of the copper catalyst. With 10 mol% of the catalyst, full conversion can be achieved in less than 10 minutes at 45°C, and thus makes this procedure potentially suited for the preparation of 18F-labeled PET probes. As a result of the mild reaction conditions, only the substitution products are observed with no evidence of common side reactions, such as elimination. Reported is a preliminary study of the reaction scope, which demonstrates that the fluorination can be performed in the presence of a wide range of functional groups. Evidence suggests an unusual role of the [IPrCuOTf] catalyst as a phase-transfer catalyst and points to [IPrCuF] as the active fluorinating reagent (IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene).
- Dang, Hester,Mailig, Melrose,Lalic, Gojko
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p. 6473 - 6476
(2014/06/24)
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- Synthesis and structure-activity relationship studies of conformationally flexible tetrahydroisoquinolinyl triazole carboxamide and triazole substituted benzamide analogues as σ2 receptor ligands
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Two novel classes of compounds targeting the sigma-2 (σ2) receptor were synthesized, and their bioactivities to binding σ1 and σ2 receptors were measured. Four novel triazole carboxamide analogues, 24d, 24e, 24f, and 39c, demonstrated high affinity and selectivity for the σ2 receptor. These data suggest 11C-labeled versions of these compounds may be potential σ2-selective radiotracers for imaging the proliferative status of solid tumors.
- Bai, Suping,Li, Shihong,Xu, Jinbin,Peng, Xin,Sai, Kiran,Chu, Wenhua,Tu, Zhude,Zeng, Chenbo,Mach, Robert H.
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supporting information
p. 4239 - 4251
(2014/06/09)
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- Synthesis and characterization of a novel series of agonist compounds as potential radiopharmaceuticals for imaging dopamine D2/3 receptors in their high-affinity state
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Imaging of dopamine D2/3 receptors (D2/3R) can shed light on the nature of several neuropsychiatric disorders in which dysregulation of D2/3R signaling is involved. Agonist D2/3 tracers for PET/SPECT imaging are considered to be superior to antagonists because they are more sensitive to dopamine concentrations and may selectively label the high-affinity receptor state. Carbon-11-labeled D2/3R agonists have been developed, but these short-lived tracers can be used only in centers with a cyclotron. Here, we report the development of a series of novel D2R agonist compounds based on the 2-aminomethylchromane (AMC) scaffold that provides ample opportunities for the introduction of longer-lived [ 18F] or [123I]. Binding experiments showed that several AMC compounds have a high affinity and selectivity for D2/3R and act as agonists. Two fluorine-containing compounds were [18F]-labeled, and both displayed specific binding to striatal D2/3R in rat brain slices in vitro. These findings encourage further in vivo evaluations.
- Van Wieringen, Jan-Peter,Shalgunov, Vladimir,Janssen, Henk M.,Fransen, P. Michel,Janssen, Anton G. M.,Michel, Martin C.,Booij, Jan,Elsinga, Philip H.
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p. 391 - 410
(2014/02/14)
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- Synthesis of a non-peptidic PET tracer designed for α 5β1 integrin receptor
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Arginine-glycine-aspartic acid (RGD)-containing peptides have been traditionally used as PET probes to noninvasively image angiogenesis, but recently, small selective molecules for α5β1 integrin receptor have been developed with prom
- Monaco, Alessandra,Michelin, Olivier,Prior, John,Rueegg, Curzio,Scapozza, Leonardo,Seimbille, Yann
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p. 365 - 370
(2014/06/10)
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- Acidic-pH-activatable fluorescence probes for visualizing exocytosis dynamics
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Live imaging of exocytosis dynamics is crucial for a precise spatiotemporal understanding of secretion phenomena, but current approaches have serious limitations. We designed and synthesized small-molecular fluorescent probes that were chemically optimized for sensing acidic intravesicular pH values, and established that they can be used to sensitively and reliably visualize vesicular dynamics following stimulation. This straightforward technique for the visualization of exocytosis as well as endocytosis/reacidification processes with high spatiotemporal precision is expected to be a powerful tool for investigating dynamic cellular phenomena involving changes in the pH value.
- Asanuma, Daisuke,Takaoka, Yousuke,Namiki, Shigeyuki,Takikawa, Kenji,Kamiya, Mako,Nagano, Tetsuo,Urano, Yasuteru,Hirose, Kenzo
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supporting information
p. 6085 - 6089
(2014/06/23)
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- Development of [18F]-labeled pyrazolo[4,3-e ]-1,2,4-triazolo[1, 5-c ]pyrimidine (SCH442416) analogs for the imaging of cerebral adenosine A 2A receptors with positron emission tomography
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Cerebral adenosine A2A receptors (A2ARs) are attractive therapeutic targets for the treatment of neurodegenerative and psychiatric disorders. We developed high affinity and selective compound 8 (SCH442416) analogs as in vivo probes for A2ARs using PET. We observed the A2AR-mediated accumulation of [18F] fluoropropyl ([18F]-10b) and [18F]fluoroethyl ([ 18F]-10a) derivatives of 8 in the brain. The striatum was clearly visualized in PET and in vitro autoradiography images of control animals and was no longer visible after pretreatment with the A2AR subtype-selective antagonist KW6002. In vitro and in vivo metabolite analyses indicated the presence of hydrophilic (radio)metabolite(s), which are not expected to cross the blood-brain-barrier. [18F]-10b and [18F]-10a showed comparable striatum-to-cerebellum ratios (4.6 at 25 and 37 min post injection, respectively) and reversible binding in rat brains. We concluded that these compounds performed equally well, but their kinetics were slightly different. These molecules are potential tools for mapping cerebral A2ARs with PET.
- Khanapur, Shivashankar,Paul, Soumen,Shah, Anup,Vatakuti, Suresh,Koole, Michel J. B.,Zijlma, Rolf,Dierckx, Rudi A. J. O.,Luurtsema, Gert,Garg, Prabha,Van Waarde, Aren,Elsinga, Philip H.
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p. 6765 - 6780
(2014/09/29)
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- Synthesis and evaluation of new 18F-labelled acetamidobenzoxazolone-based radioligands for imaging of the translocator protein (18 kDa, TSPO) in the brain
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The visualization of the activated microglia/TSPO is one of the main aspects of neuroimaging. Here we describe two new 18F-labelled molecules, 2-[5-(4-[18F]fluoroethoxyphenyl)- ([18F]2) and 2-[5-(4-[18F]fluoropr
- Tiwari, Anjani K.,Fujinaga, Masayuki,Yui, Joji,Yamasaki, Tomoteru,Xie, Lin,Kumata, Katsushi,Mishra, Anil K.,Shimoda, Yoko,Hatori, Akiko,Ji, Bin,Ogawa, Masanao,Kawamura, Kazunori,Wang, Feng,Zhang, Ming-Rong
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p. 9621 - 9630
(2015/02/19)
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- IN VIVO IMAGING METHOD OF MOOD DISORDERS
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The present invention provides a method useful in the diagnosis and/or monitoring of mood disorders wherein there is an abnormal expression of PBR. The method of the invention is useful in the differential diagnosis of said mood disorders and other condit
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Paragraph 0168
(2013/07/19)
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- Fully automated radiosynthesis of [1-(2-[18F]fluoroethyl),1H[1, 2,3]triazole 4-ethylene] triphenylphosphonium bromide as a potential positron emission tomography tracer for imaging apoptosis
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A novel phosphonium salt bearing a fluorine-18 labelled triazole has been designed as a potential imaging agent for apoptosis. The radiosynthesis of [1-(2-[18F]fluoroethyl),1H[1,2,3]triazole 4-ethylene] triphenylphosphonium bromide ([18F]MitoPhos-01) has been carried out on a fully automated system in a two-step reaction. Radiolabelling an ethyl azide and then carrying out a copper-mediated 1,3-cycloaddition reaction has allowed for total synthesis time to be slightly more than 1 h from aqueous [18F]fluoride. After purification by HPLC, the average radiochemical yield was determined to be 9% (not decay corrected); the specific activity was on average 70 GBq/μmol at the end of synthesis, and the radiochemical purity was >99%. A novel phosphonium salt bearing a fluorine-18 labelled triazole has been designed as a potential imaging agent for apoptosis. The radiosynthesis of [1-(2-[18F]fluoroethyl),1H[1,2,3]triazole 4-ethylene] triphenylphosphonium bromide ([18F]MitoPhos-01) has been carried out on a fully automated system in a two-step reaction, with the average radiochemical yield determined to be 9% (not decay corrected); the specific activity being around 70 GBq/μmol at the end of synthesis and the radiochemical purity above 99%. Copyright
- Haslop, Anna,Gee, Antony,Plisson, Christophe,Long, Nicholas
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p. 313 - 316
(2013/07/26)
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