- Synthesis and biological evaluation of 18F-labeled fluoroethoxy tryptophan analogues as potential PET tumor imaging agents
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As a continuation of our research efforts toward the development of tryptophan-based radiotracers for tumor imaging with positron emission tomography (PET), three new fluoroethoxy tryptophan analogues were synthesized and evaluated in vivo. These new tracers (namely, 4-(2-[18F]fluoroethoxy)-DL-tryptophan ([18F]4-FEHTP), 6-(2-[18F]fluoroethoxy)-DL-tryptophan ([18F]6-FEHTP), and 7-(2-[18F]fluoroethoxy)-DL-tryptophan ([18F]7-FEHTP) carry the fluoroethoxy side chain either at positions 4-, 6-, or 7- of the indole core. Reference compounds and precursors were synthesized by multistep approaches. Radiosynthesis was accomplished by no-carrier-added nucleophilic 18F-fluorination following either an indirect approach (O-alkylation of the corresponding hydroxytryptophan with [18F]fluoroethyltosylate) or a direct approach (nucleophilic [18F] fluorination using a protected mesyl precursor). Radiochemical yields (decay corrected) for both methods were in the range of 10-18%. Small animal PET imaging with xenograft-bearing mice revealed the highest tumor/background ratio for [18F]6-FEHTP which, in a direct comparison, outperformed the other two tryptophan tracers and also the well-established tyrosine analogue O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]L-FET). Investigation of the transport mechanism of [18F]6-FEHTP in small cell lung cancer cells (NCI-H69) revealed that it is most probably taken up exclusively via the large neutral amino acid transporter(s) (LAT).
- Chiotellis, Aristeidis,Muller, Adrienne,Mu, Linjing,Keller, Claudia,Schibli, Roger,Kramer, Stefanie D.,Ametamey, Simon M.
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- Synthesis and radiopharmacological characterisation of a fluorine-18-labelled azadipeptide nitrile as a potential PET tracer for invivo imaging of cysteine cathepsins
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A fluorinated cathepsin inhibitor based on the azadipeptide nitrile chemotype was prepared and selected for positron emission tomography (PET) tracer development owing to its high affinity for the oncologically relevant cathepsins L, S, K and B. Labelling with fluorine-18 was accomplished in an efficient and reliable two-step, one-pot radiosynthesis by using 2-[18F]fluoroethylnosylate as a prosthetic agent. The pharmacokinetic properties of the resulting radiotracer compound were studied invitro, exvivo and invivo in normal rats by radiometabolite analysis and small-animal positron emission tomography. These investigations revealed rapid conjugate formation of the tracer with glutathione in the blood, which is associated with slow blood clearance. The potential of the developed 18F-labelled probe to image tumour-associated cathepsin activity was investigated by dynamic small-animal PET imaging in nude mice bearing tumours derived from the human NCI-H292 lung carcinoma cell line. Computational analysis of the obtained image data indicated the time-dependent accumulation of the radiotracer in the tumours. The expression of the target enzymes in the tumours was confirmed by immunohistochemistry with specific antibodies. This indicates that azadipeptide nitriles have the potential to target thiol-dependent cathepsins invivo despite their disadvantageous pharmacokinetics.
- Loeser, Reik,Bergmann, Ralf,Frizler, Maxim,Mosch, Birgit,Dombrowski, Lilli,Kuchar, Manuela,Steinbach, Joerg,Guetschow, Michael,Pietzsch, Jens
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- 18F-Labeled Pyrido[3,4-d]pyrimidine as an Effective Probe for Imaging of L858R Mutant Epidermal Growth Factor Receptor
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In nonsmall-cell lung carcinoma patients, L858R mutation of epidermal growth factor receptor (EGFR) is often found, and molecular target therapy using EGFR tyrosine kinase inhibitors is effective for the patients. However, the treatment frequently develops drug resistance by secondary mutation, of which approximately 50% is T790M mutation. Therefore, the ability to predict whether EGFR will undergo secondary mutation is extremely important. We synthesized a novel radiofluorinated 4-(anilino)pyrido[3,4-d]pyrimidine derivative ([18F]APP-1) and evaluated its potential as a positron emission tomography (PET) imaging probe to discriminate the difference in mutations of tumors. EGFR inhibition assay, cell uptake, and biodistribution study showed that [18F]APP-1 binds specifically to the L858R mutant EGFR but not to the L858R/T790M mutant. Finally, on PET imaging study using [18F]APP-1 with tumor-bearing mice, the H3255 tumor (L858R mutant) was more clearly visualized than the H1975 tumor (L858R/T790M mutant).
- Kimura, Hiroyuki,Okuda, Haruka,Ishiguro, Masumi,Arimitsu, Kenji,Makino, Akira,Nishii, Ryuichi,Miyazaki, Anna,Yagi, Yusuke,Watanabe, Hiroyuki,Kawasaki, Ikuo,Ono, Masahiro,Saji, Hideo
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- An efficient method for enhancing the reactivity and flexibility of [18F]fluoride towards nucleophilic substitution using tetraethylammonium bicarbonate
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The standard method used to generate reactive [18F]fluoride for [18F]radiolabelling is to trap it on an anion-exchange cartridge then elute it with a basic aqueous solution, which is then subjected to azeotropic evaporation to remove
- Brichard, Laurent,Aigbirhio, Franklin I.
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- Synthesis and evaluation of [18F]FETLOs and [18F]AMBF3LOS as novel 18F-labelled losartan derivatives for molecular imaging of angiotensin II type 1 receptors
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Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT1Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT1R using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, [18F]fluoroethyl-losartan ([18F]FEtLos) and [18F]ammoniomethyltrifluoroborate-losartan ([18F]AMBF3Los). [18F]FEtLos was radiolabeled by 18F-fluoroalkylation of losartan potassium using the prosthetic group 2-[18F]fluoroethyl tosylate; whereas [18F]AMBF3Los was prepared following an one-step 18F-19F isotopic exchange reaction, in an overall yield of 2.7 ± 0.9% and 11 ± 4%, respectively, with high radiochemical purity (>95%). Binding competition assays in AT1R-expressing membranes showed that AMBF3Los presented an almost equivalent binding affinity (Ki 7.9 nM) as the cold reference Losartan (Ki 1.5 nM), unlike FEtLos (Ki 2000 nM). In vitro and in vivo assays showed that [18F]AMBF3Los displayed a good binding affinity for AT1R-overexpressing CHO cells and was able to specifically bind to renal AT1R. Hence, our data demonstrate [18F]AMBF3Los as a new tool for PET imaging of AT1R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases.
- Ortega Pijeira, Martha Sahylí,Gon?alves Nunes, Paulo Sérgio,Dos Santos, Sofia Nascimento,Zhang, Zhengxing,Nario, Arian Pérez,Perini, Efrain Araujo,Turato, Walter Miguel,Riera, Zalua Rodríguez,Chammas, Roger,Elsinga, Philip H.,Lin, Kuo-Shyan,Carvalho, Ivone,Bernardes, Emerson Soares
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- 18F-Labeled indole-based analogs as highly selective radioligands for imaging sigma-2 receptors in the brain
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We have designed and synthesized a series of indole-based σ2 receptor ligands containing 5,6-dimethoxyisoindoline or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline as pharmacophore. In vitro competition binding assays showed that all ten ligands
- Wang, Liang,Ye, Jiajun,He, Yingfang,Deuther-Conrad, Winnie,Zhang, Jinming,Zhang, Xiaojun,Cui, Mengchao,Steinbach, J?rg,Huang, Yiyun,Brust, Peter,Jia, Hongmei
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- Synthesis, radiofluorination, and in vivo evaluation of novel fluorinated and iodinated radiotracers for PET imaging and targeted radionuclide therapy of melanoma
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Our project deals with a multimodal approach using a single fluorinated and iodinated melanin-targeting structure and offering both imaging (positron emission tomography (PET)/fluorine-18) and treatment (targeted radionuclide therapy/iodine-131) of melano
- Billaud, Emilie M. F.,Rbah-Vidal, Latifa,Vidal, Aurélien,Besse, Sophie,Tarrit, Sébastien,Askienazy, Serge,Maisonial, Aurélie,Moins, Nicole,Madelmont, Jean-Claude,Miot-Noirault, Elisabeth,Chezal, Jean-Michel,Auzeloux, Philippe
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- 3-(4-(6-Fluoroalkoxy-3,4-dihydroisoquinoline-2(1H)-yl)cyclohexyl)-1H-indole-5-carbonitriles for SERT imaging: Chemical synthesis, evaluation in vitro and radiofluorination
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Aminocyclohexyl indoles bind with high affinity and specificity toward the serotonin transporter (SERT). Based on this structural lead, we designed fluoroalkoxydihydroisoquinoline-cyclohexyl indole carbonitriles for future application as 18F-labeled tracers for SERT imaging by PET. Six compounds, three pairs of cis- and trans-isomer derivatives, respectively, were synthesized and evaluated in vitro. The chemistry of the new compounds, their affinity and specificity data, the general route to the phenolic precursor for labeling, and the successful 18F-fluoroalkylation of one pair of compounds are described herein.
- Funke, Uta,Fischer, Steffen,Hiller, Achim,Scheunemann, Matthias,Deuther-Conrad, Winnie,Brust, Peter,Steinbach, Joerg
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- Synthesis and biological characterization of a promising F-18 PET tracer for vesicular acetylcholine transporter
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Nine fluorine-containing vesicular acetylcholine transporter (VAChT) inhibitors were synthesized and screened as potential PET tracers for imaging the VAChT. Compound 18a was one of the most promising carbonyl-containing benzovesamicol analogs; the minus
- Tu, Zhude,Zhang, Xiang,Jin, Hongjun,Yue, Xuyi,Padakanti, Prashanth K.,Yu, Lihai,Liu, Hui,Flores, Hubert P.,Kaneshige, Kota,Parsons, Stanley M.,Perlmutter, Joel S.
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- Efficient alkali iodide promoted 18F-fluoroethylations with 2-[18F]fluoroethyl tosylate and 1-bromo-2-[18F]fluoroethane
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Radiochemical 18F-fluorination yields of several compounds using secondary labelling precursors 2-[18F]fluoroethyl tosylate ([18F]FETos) and 1-bromo-2-[18F]fluoroethane ([18F]BFE) could be considerably enhanced by the addition of an alkali iodide. The rad
- Bauman, Andreas,Piel, Markus,Schirrmacher, Ralf,Roesch, Frank
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- Synthesis and biological evaluation of positron emission tomography radiotracers targeting serotonin 4 receptors in brain: [18F]MNI-698 and [18F]MNI-699
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Two new benzodioxane derivatives were synthesized as candidates to image the serotonin 4 receptors by positron emission tomography (PET) and radiolabeled with fluorine-18 via a two-step procedure. Competition binding assays demonstrated that MNI-698 and M
- Caille, Fabien,Morley, Thomas J.,Tavares, Adriana Alexandre S.,Papin, Caroline,Twardy, Nicole M.,Alagille, David,Lee, H. Sharon,Baldwin, Ronald M.,Seibyl, John P.,Barret, Olivier,Tamagnan, Gilles D.
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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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- Synthesis and evaluation of 5,7-dichloro-4-(3-{4-[4-(2-[18F]fluoroethyl)-piperazin-1-yl]-phenyl}-ureido)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid as a potential NMDA ligand to study glutamatergic neurotransmission in vivo
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The neurotransmitter glutamate is thought to be crucially involved in a huge number of neurological and psychiatric disorders, such as Morbus Parkinson, Alzheimer's disease and schizophrenia. Aiming at an improved diagnostic tool for PET a new [18F]fluori
- Piel, Markus,Schirrmacher, Ralf,Hoehnemann, Sabine,Hamkens, Wilhelm,Kohl, Beate,Jansen, Michaela,Schmitt, Ullrich,Lueddens, Hartmut,Dannhardt, Gerd,Roesch, Frank
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- Synthesis and biological evaluation of a fluorine-18 derivative of dasatinib
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Tyrosine kinases often play pivotal roles in the pathogenesis of cancer and are good candidates for therapeutic intervention and targeted molecular imaging. The precursor synthesis, radiosynthesis, and biological characterization of a fluorine-18 analog o
- Veach, Darren R.,Namavari, Mohammad,Pillarsetty, Nagavarakishore,Santos, Elmer B.,Beresten-Kochetkov, Tatiana,Lambek, Caryl,Punzalan, Blesida J.,Antczak, Christophe,Smith-Jones, Peter M.,Djaballah, Hakim,Clarkson, Bayard,Larson, Steven M.
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- FE@SNAP - A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): Microfluidic and vessel-based approaches
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Changes in the expression of the melanin concentrating hormone receptor 1 (MCHR1) are involved in a variety of pathologies, especially obesity and anxiety disorders. To monitor these pathologies in-vivo positron emission tomography (PET) is a suitable met
- Philippe, Cécile,Ungersboeck, Johanna,Schirmer, Eva,Zdravkovic, Milica,Nics, Lukas,Zeilinger, Markus,Shanab, Karem,Lanzenberger, Rupert,Karanikas, Georgios,Spreitzer, Helmut,Viernstein, Helmut,Mitterhauser, Markus,Wadsak, Wolfgang
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- Synthesis and evaluation of a 18F-labeled spirocyclic piperidine derivative as promising σ1receptor imaging agent
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Several spirocyclic piperidine derivatives were designed and synthesized as σ1receptor ligands. In vitro competition binding assays showed that the fluoroalkoxy analogues with small substituents possessed high affinity towards σ1rece
- Chen, Yuan-Yuan,Wang, Xia,Zhang, Jin-Ming,Deuther-Conrad, Winnie,Zhang, Xiao-Jun,Huang, Yiyun,Li, Yan,Ye, Jia-Jun,Cui, Meng-Chao,Steinbach, J?rg,Brust, Peter,Liu, Bo-Li,Jia, Hong-Mei
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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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- SYNTHESIZING PET TRACERS USING [F-18]SULFONYL FLUORIDE AS A SOURCE OF [F-18]FLUORIDE
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The present disclosure relates to the methods for the preparation of reactive [F-18]fluoride in a form of [F-18]sulfonyl fluoride suitable for efficient radiolabeling without an azeotropic evaporation step by the use of anion exchange resin and sulfonyl c
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Paragraph 0098
(2018/01/11)
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- Nuclear Medicine Diagnostic Imaging Agent
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Provided is a radioactive labeled compound capable of detecting a secondary mutation of an epidermal growth factor receptor, where the compound is represented by Formula (1) or a pharmaceutically acceptable salt thereof, where Y, L1, R1 /
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Paragraph 0131; 0132
(2017/01/23)
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- Nuclear Medicine Diagnostic Imaging Agent
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Provided is a radioactive labeled compound capable of detecting a secondary mutation of an epidermal growth factor receptor, where the compound is represented by Formula (1) or a pharmaceutically acceptable salt thereof, where R1, R2
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Paragraph 0148
(2017/01/23)
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- ALPHA-SYNUCLEIN LIGANDS
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The present invention generally relates to various compounds that are useful as α-synuclein ligands. The invention further relates to methods of using these compounds and their radiolabeled analogs for the detection of synucleinopathies, including Parkinson's disease (PD).
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Paragraph 0291-0293
(2017/08/01)
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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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- Automation of [18F]fluoroacetaldehyde synthesis: application to a recombinant human interleukin-1 receptor antagonist (rhIL-1RA)
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[18F]Fluoroacetaldehyde is a biocompatible prosthetic group that has been implemented pre-clinically using a semi-automated remotely controlled system. Automation of radiosyntheses permits use of higher levels of [18F]fluoride whilst
- Morris, Olivia,McMahon, Adam,Boutin, Herve,Grigg, Julian,Prenant, Christian
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p. 277 - 283
(2016/07/10)
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- Design, Synthesis, and in Vitro and in Vivo Evaluation of an 18F-Labeled Sphingosine 1-Phosphate Receptor 1 (S1P1) PET Tracer
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Sphingosine 1-phosphate receptor 1 (S1P1) plays a pivotal signaling role in inflammatory response; because S1P1 modulation has been identified as a therapeutic target for various diseases, a PET tracer for S1P1 would be a useful tool. Fourteen fluorine-containing analogues of S1P ligands were synthesized and their in vitro binding potency measured; four had high potency and selectivity for S1P1 (S1P1 IC50 100-fold selectivity for S1P1 over S1P2 and S1P3). The most potent ligand, 28c (IC50 = 2.63 nM for S1P1) was 18F-labeled and evaluated in a mouse model of LPS-induced acute liver injury to determine its S1P1-binding specificity. The results from biodistribution, autoradiography, and microPET imaging showed higher [18F]28c accumulation in the liver of LPS-treated mice than controls. Increased expression of S1P1 in the LPS model was confirmed by immunohistochemical analysis (IHC). These data suggest that [18F]28c is a S1P1 PET tracer with high potential for imaging S1P1 in vivo.
- Rosenberg, Adam J.,Liu, Hui,Jin, Hongjun,Yue, Xuyi,Riley, Sean,Brown, Steven J.,Tu, Zhude
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p. 6201 - 6220
(2016/07/26)
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- Crown ether cyclic quinazoline compound, preparation method therefor and application thereof in preparing tumor therapy and imaging drug
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The invention relates to a crown ether cyclic quinazoline derivative and medicinal salts thereof using in tumor therapy and imaging. The crown ether cyclic quinazoline compound is characterized in that a 2-, 3-, 4- substituted aniline is disposed at one end; a 6-, 7- substituted crown ether cyclic quinazoline structure is disposed at the other end; the substituent group R1 is located on the fourth-position aniline of a quinazoline mother ring and is 2-, 3-, 4- substituted alkoxy; and the crown ether cycle is located at the 6, 7 position of the mother ring, and is a 9-crown-3, 12-crown-4 and 15-crown-5, and the structural formula is formula I. The experimental result of antitumor activity in vitro of nonradioactive isotope labeling compounds shows that the compounds are good in inhibitory effect for four kind of cancer cells namely HepG2, A549, sy5y and DU145, and have the potential as cancer treatment medicine; and the body distribution experiment of 18F or 125I labeling compounds show that the compounds are higher in ingestion and certain detention in tumors and faster in blood clearance and have potential applied to tumor imaging.
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Paragraph 0116; 0117; 0118
(2016/10/09)
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- Design, synthesis and evaluation of18F-labeled bradykinin B1 receptor-targeting small molecules for PET imaging
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Two fluorine-18 (18F) labeled bradykinin B1 receptor (B1R)-targeting small molecules,18F-Z02035 and18F-Z02165, were synthesized and evaluated for imaging with positron emission tomography (PET). Z02035 and Z02165 were deri
- Zhang, Zhengxing,Kuo, Hsiou-Ting,Lau, Joseph,Jenni, Silvia,Zhang, Chengcheng,Zeisler, Jutta,Bénard, Fran?ois,Lin, Kuo-Shyan
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p. 4095 - 4100
(2016/08/01)
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- Model 18 F mark 4-amino-quinazoline derivatives and its preparation method and tumor PET imaging applications
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The invention provides novel F marked 4-aminoquinazoline compounds. The novel F marked 4-aminoquinazoline compounds are characterized in that one end of each of the novel F marked 4-aminoquinazoline compounds has a F substituted alkyloxy structure; the other end of each of the compounds has a 6,7-substituted quinazoline structure, and a substituent R1 is positioned in the 3 position of a 4-aminobenzene ring which is the quinazoline maternal, and is H, F, Cl, Br, I, a trifluoromethyl group or an acetenyl group; a substituent R2 is positioned in the 4 position of the 4-aminobenzene ring which is the quinazoline maternal, and is H, F, Cl, Br, a methyl group, a methoxy group, a 3-fluorophenoxyl group, or a 2-pyridyloxy group; and n is 1-5. The structural formula of the compounds is shown as A in the specification. Results of experiments show that the precursor of the marker of the compounds is easy to synthesize, marks through using a two-step method and has a high marking rate. The compounds have a good bioactivity, for example, the compounds have high absorption and slow removal in tumor tissues and low intake and fast removal in normal tissues and blood, so the compounds have a high tumor/background ratio, and especially have a high tumor/blood ratio, a high tumor/flesh ratio and a high tumor/brain ration, are in favor of the PET tumor development, and perform a huge potential as a brain tumor developer.
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Paragraph 0114-0116
(2016/11/28)
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- Model 18 F mark substituted [...] compound and its preparation method and tumor PET imaging applications
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The invention provides a novel F marked substituted quinazoline compound. The novel F marked substituted quinazoline compound is characterized in that one end of the novel F marked substituted quinazoline compound has a F substituted alkyloxy structure; the other end of the compound has a 6,7-substituted quinazoline structure, and a substituent R1 is positioned in the 4 position of a quinazoline maternal, and is a 2-, 3-, 4-F substituted alkyloxy group; and a substituent R2 is positioned in the 6 position of the quinazoline maternal, and is a methoxyethoxy group, a methoxy group, or a morpholinepropanolato group. The structural formula of the compound is shown as A in the specification. Results of experiments show that the compound has the advantages of good bioactivity, good serum stability, low intake in tissues of the liver and the like, and high enrichment and slow removal rate in tumors, and the marking precursor of the compound has the advantages of easy synthesis, extremely high marking rate and the like, so the compound has a huge potential for the tumor PET development.
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Paragraph 0099-0102
(2017/01/09)
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- Imino acid PET imaging agent and its preparation method and application
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The invention discloses an amino acid positron emission tomography (PET) imaging agent, and a preparation method and application thereof. The imaging agent belongs to the field of N-substituted positron nuclide labeled glutamic acid compound and has a str
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Paragraph 0047; 0048
(2017/01/12)
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- METHOD OF SYNTHESIZING FLUORINE-18 LABELED RADIOPHARMACEUTICALS IN ETHANOL AND WATER
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A method of preparing fluorine-18 labeled radiopharmaceuticals (18F-radiopharmaceuticals) is disclosed. More particularly, the present invention relates to a method of preparing an 18F-radiopharmaceutical by reacting a salt containing fluorine-18 (18F) with an alkyl halide or an alkyl sulfonate in the presence of water and ethanol to obtain a high yield of the 18F-radiopharmaceutical. The synthetic method eliminates the use of toxic and/or environmentally-unfriendly organic solvents.
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- For radioactive-derwed Pyridinil deriv. in vivo imaging
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The present invention provides a novel radiolabeled aryloxyalinine derivative suitable for in vivo imaging. In comparison to known aryloxyalinine derivative in vivo imaging agents, the in vivo imaging agent of the present invention has better properties for in vivo imaging. The in vivo imaging agent of the present invention demonstrates good selective binding to the peripheral benzodiazepine receptor (PBR), in combination with good brain uptake and in vivo kinetics following administration to a subject.
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Paragraph 0187; 0188; 0189
(2016/10/09)
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- 18F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ1 Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent
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We report the syntheses and evaluation of series of novel piperidine compounds with low lipophilicity as σ1 receptor ligands. 8-(4-(2-Fluoroethoxy)benzyl)-1,4-dioxa-8-azaspiro[4.5]decane (5a) possessed high affinity (Ki = 5.4 ± 0.4 nM) for σ1 receptors and selectivity for σ2 receptors (30-fold) and the vesicular acetylcholine transporter (1404-fold). [18F]5a was prepared using a one-pot, two-step labeling procedure in an automated synthesis module, with a radiochemical purity of >95%, and a specific activity of 25-45 GBq/μmol. Cellular association, biodistribution, and autoradiography with blocking experiments indicated specific binding of [18F]5a to σ1 receptors in vitro and in vivo. Small animal positron emission tomography (PET) imaging using mouse tumor xenograft models demonstrated a high accumulation in human carcinoma and melanoma. Treatment with haloperidol significantly reduced the accumulation of the radiotracer in tumors. These findings suggest that radiotracer with suitable lipophilicity and appropriate affinity for σ1 receptors could be used for tumor imaging.
- Xie, Fang,Bergmann, Ralf,Kniess, Torsten,Deuther-Conrad, Winnie,Mamat, Constantin,Neuber, Christin,Liu, Boli,Steinbach, J?rg,Brust, Peter,Pietzsch, Jens,Jia, Hongmei
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p. 5395 - 5407
(2015/08/03)
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- Fluorine-18 labeled rhodamine derivatives for imaging with positron emission tomography
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The present invention is directed toward novel fluorine-18 labeled rhodamine dye derivatives and methods of making the same. The present invention is also directed toward methods of using novel fluorine-18 labeled rhodamine dye derivatives as positron emi
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Page/Page column 16
(2015/09/28)
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- Fluorine-18 and carbon-11 labeled radioligands for positron emission tomography (PET) imaging for LRRK2
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A method for positron emission tomography (PET) imaging of LRRK2 in tissue of a subject, the method comprising: administering a compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt thereof to the subject, wherein the com
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Page/Page column 73
(2015/11/16)
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- Green approaches to late-stage fluorination: Radiosyntheses of 18F-labelled radiopharmaceuticals in ethanol and water
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Green strategies for late-stage fluorination with 18F, in which ethanol and water are the only solvents used throughout the entire radiolabeling process (azeotropic drying, nucleophilic fluorination, purification and formulation), have been dev
- Stewart, Megan N.,Hockley, Brian G.,Scott, Peter J. H.
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supporting information
p. 14805 - 14808
(2015/10/05)
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- Synthesis of fluorine-containing phosphodiesterase 10A (PDE10A) inhibitors and the in vivo evaluation of F-18 labeled PDE10A PET tracers in rodent and nonhuman primate
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A series of fluorine-containing PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [11C]MP-10. Twenty of the 22 new analogues had high potency and selectivity for PDE10A: 18a-j, 19d-j, 20a-b, and 21b had IC50 values 18F]18a-e, [18F]18g, and [18F]20a were radiosynthesized by 18F-introduction onto the quinoline rather than the pyrazole moiety of the MP-10 pharmacophore and performed in vivo evaluation. Biodistribution studies in rats showed ~2-fold higher activity in the PDE10A-enriched striatum than nontarget brain regions; this ratio increased from 5 to 30 min postinjection, particularly for [18F]18a-d and [18F]20a. MicroPET studies of [18F]18d and [18F]20a in nonhuman primates provided clear visualization of striatum with suitable equilibrium kinetics and favorable metabolic stability. These results suggest this strategy may identify a 18F-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington's disease and schizophrenia.
- Li, Junfeng,Zhang, Xiang,Jin, Hongjun,Fan, Jinda,Flores, Hubert,Perlmutter, Joel S.,Tu, Zhude
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p. 8584 - 8600
(2015/11/25)
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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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- RADIOLABELED 5-HT6 LIGANDS
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Compounds of formula (I) are disclosed Compounds of formula (I) are useful in treating conditions and disorders prevented by or ameliorated by 5-HT6 receptor ligands. Radiolabeled compounds of formula (I) are also useful as diagnostic tools as
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Paragraph 0217-0218
(2014/05/08)
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- Synthesis and evaluation of three structurally related 18F- labeled orvinols of different intrinsic activities: 6-O-[18F] fluoroethyl-diprenorphine ([18F]FDPN), 6-O-[18F] fluoroethyl-buprenorphine ([18F]FBPN), and 6-O-[18F] fluoroethyl-phenethyl-orvinol ([18F]FPEO)
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We report the synthesis and biological evaluation of a triplet of 6-O- 18F-fluoroethylated derivatives of structurally related orvinols that span across the full range of intrinsic activities, the antagonist diprenorphine, the partial agonist buprenorphine, and the full agonist phenethyl-orvinol. [18F]fluoroethyl-diprenorphine, [ 18F]fluoroethyl-buprenorphine, and [18F]fluoroethyl- phenethyl-orvinol were prepared in high yields and quality from their 6-O-desmethyl-precursors. The results indicate suitable properties of the three 6-O-18F-fluoroethylated derivatives as functional analogues to the native carbon-11 labeled versions with similar pharmacological properties.
- Schoultz, Bent W.,Hj?rnevik, Trine,Reed, Brian J.,Marton, János,Coello, Christopher S.,Willoch, Frode,Henriksen, Gjermund
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supporting information
p. 5464 - 5469
(2014/07/08)
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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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- Radiosynthesis of 18F-labeled N-desmethyl-loperamide analogues for prospective molecular imaging radiotracers
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A simple procedure for preparing fluoroethyl-N-desmethyl-loperamide 4 and its analogue 5 was developed. Standard compound 4 was synthesized in useful yields for radiolabeling analysis. [N-Ethyl-18F]N-desmethyl-loperamide, 3, was rapidly and efficiently labeled with no-carrier added fluorine-18 (t 1/2 = 109.7 min) by treatment of readily prepared [ 18F]1-bromo-2-fluoro ethane with a N-desmethyl-loperamide precursor at a consistent 7% radiochemical yield. This procedure was also adapted to the radiosynthesis of 3 by [18F]ethylene tosylate, but at a lower 3% radiochemical yield. Copyright
- Bao, Xiaofeng,Liu, Duliang
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p. 1412 - 1415
(2013/04/23)
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- Synthesis and in vivo evaluation of [18F]2-(4-(4-(2-(2- fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H) -dione ([18F]FECUMI-101) as an imaging probe for 5-HT1A receptor agonist in nonhuman prim
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The 5-HT1AR partial agonist PET radiotracer, [ 11C]CUMI-101, has advantages over an antagonist radiotracer as it binds preferentially to the high affinity state of the receptor and thereby provides more functionally meaningful inform
- Majo, Vattoly J.,Milak, Matthew S.,Prabhakaran, Jaya,Mali, Pratap,Savenkova, Lyudmila,Simpson, Norman R.,Mann, J. John,Parsey, Ramin V.,Kumar, J. S. Dileep
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p. 5598 - 5604
(2013/09/02)
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- COMPOSITIONS, METHODS, AND SYSTEMS FOR THE SYNTHESIS AND USE OF IMAGING AGENTS
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The present invention relates to systems, compositions, and methods for the synthesis and use of imaging agents, or precursors thereof. An imaging agent precursor may be converted to an imaging agent using the methods described herein. In some cases, the
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Page/Page column 222
(2013/03/26)
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- Exploration of the structure-activity relationship of a novel tetracyclic class of TSPO ligands - Potential novel positron emitting tomography imaging agents
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A series of novel TSPO ligands based on the tetracyclic class of translocator protein (TSPO) ligands first described by Okubo et al. was synthesised and evaluated as potential positron emitting tomography (PET) ligands for imaging TPSO in vivo. Fluorine-18 labelling of the molecules was achieved using direct radiolabelling or synthon based labelling approaches. Several of the ligands prepared have promising profiles as potential TSPO PET imaging ligands.
- O'Shea, Dennis,Ahmad, Rabia,Arstad, Erik,Avory, Michelle,Chau, Wai-Fung,Durrant, Clare,Hirani, Ella,Jones, Paul A.,Khan, Imtiaz,Luthra, Sajinder K.,Mantzilas, Dimitrios,Morisson-Iveson, Véronique,Passmore, Joanna,Robins, Edward G.,Shan, Bo,Wadsworth, Harry,Walton, Sarah,Zhao, Yongjun,Trigg, William
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p. 2368 - 2372
(2013/05/08)
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- METHOD FOR THE SYNTHESIS OF 18F-LABELLED BIOMOLECULES
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The present invention provides a method for the synthesis of 18F-labelled biomolecules, which is amenable to automation. The present invention also provides a cassette for automating the method of the invention. The method of the present invention provide
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Page/Page column 17; 18; 19; 20; 21
(2013/04/25)
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- METHOD FOR THE SYNTHESIS OF 18F-LABELLED BIOMOLECULES
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The present invention provides a method for the synthesis of 18F-labelled biomolecules, which is amenable to automation. The present invention also provides a cassette for automating the method of the invention. The method of the present invent
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Page/Page column 16; 17; 18; 19; 20
(2013/04/25)
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- Radiosynthesis and first evaluation in mice of [18F]NS14490 for molecular imaging of α7 nicotinic acetylcholine receptors
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[18F]NS14490, a new potential radiotracer for neuroimaging of α7 nicotinic acetylcholine receptors (α7 nAChRs), was synthesized and evaluated in vitro and in vivo. Radioligand binding studies using [ 3H]methyllycaconitine and NS14490
- R?tering, Sven,Scheunemann, Matthias,Fischer, Steffen,Hiller, Achim,Peters, Dan,Deuther-Conrad, Winnie,Brust, Peter
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p. 2635 - 2642
(2013/06/27)
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- Two-step radiosynthesis of [18F]FE-β-CIT and [ 18F]PR04.MZ
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The cocaine-derived dopamine reuptake inhibitors FE-β-CIT (8-(2-fluoroethyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester) (1) and PR04.MZ(8-(4-fluorobut-2-ynyl)-3-p-tolyl-8-azabicyclo[3.2. 1]octane-2-carboxylic acid methyl es
- Riss, Patrick J.,Hoehnemann, Sabine,Piel, Markus,Roesch, Frank
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p. 356 - 359
(2013/07/26)
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- Radiosynthesis and characterization of astemizole derivatives as lead compounds toward PET imaging of τ-pathology
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Formation of neurofibrillary tangles, comprising of microtubule-associated tau protein, is a hallmark of a group of neurodegenerative diseases, including Alzheimer's disease. In consequence, in vivo imaging of neurofibrillary tangles is a current focus of positron emission tomography research. Herein, development of an in vitro radioligand binding assay which uses synthetic aggregates as a model of neurofibrillary tangles is reported, together with evaluation of novel derivatives of the tau protein ligand astemizole. The Royal Society of Chemistry 2013.
- Riss, Patrick J.,Brichard, Laurent,Ferrari, Valentina,Williamson, David J.,Fryer, Tim D.,Hong, Young T.,Baron, Jean-Claude,Aigbirhio, Franklin I.
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supporting information
p. 852 - 855
(2013/08/26)
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- FLUORINE-18 AND CARBON-11 LABELED RADIOLIGANDS FOR POSITRON EMISSION TOMOGRAPHY (PET) IMAGING FOR LRRK2
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A method for positron emission tomography (PET) imaging of LRRK2 in the tissue of a subject, the method comprising: administering a compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof to the subject, where
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Page/Page column 120
(2013/06/27)
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- TRICYCLIC HETEROAROMATIC COMPOUNDS AS ALPHA-SYNUCLEIN LIGANDS
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Derivatives of phenothiazine, phenoxazine, and phenazine compounds and their use as α-synuclein ligands are described. Also described are methods of using these compounds and their radiolabeled analogs for the detection, monitoring, and treatment of synucleinopathies, including Parkinson's disease.
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-
Paragraph 0274; 0275
(2013/12/04)
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- RADIOLABELED 5-HT6 LIGANDS
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Compounds of formula (I) are disclosed Compounds of formula (I) are useful in treating conditions and disorders prevented by or ameliorated by 5-HT6 receptor ligands. Radiolabeled compounds of formula (I) are also useful as diagnostic tools as
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-
Paragraph 0198
(2014/02/15)
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- Synthesis and evaluation of novel F-18 labeled 4-aminoquinazoline derivatives: Potential PET imaging agents for tumor detection
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Three novel 18F-labeled 4-aminoquinazoline derivatives, N-(3-chloro-4-fluorophenyl)-6-(2-[18F]fluoroethoxy)-7- methoxyquinazolin-4-amine([18F]1), N-(3-ethynylphenyl)-6-(2-[ 18F]fluoroethoxy)-7-methoxyquinazolin-4-amine([18F]2), and N-(3-bromophenyl)-6-(2-[18F]fluoroethoxy)-7-methoxyquinazolin-4- amine([18F]3) were synthesized and radiolabeled by two-step reaction with overall radiochemical yield of 21-24% (without decay corrected). Then we carried out their biodistribution experiments in S180 tumor-bearing mice. Results showed that they had certain concentration accumulation in tumor and fast clearance from muscle and blood. It was encouraging that [18F]3 was competitive among three 18F-labeled 4-aminoquinazoline derivatives in some aspects such as tumor/muscle uptake ratio reaching 7.70 at 60 min post-injection, tumor/blood uptake ratio reaching 6.61 at 120 min post-injection. So we compared radioactivity characteristics of [ 18F]3 with those of [18F]-FDG and L-[18F]-FET in the same animal model. The absolute radioactivity uptake of [18F]3 in tumor reached 3.31 at 60 min p.i., which was slightly higher than [ 18F]-FDG (2.16) and L-[18F]-FET (2.75) at the same time phase. For [18F]3, tumor/muscle uptake ratio peaked 7.70 at 60 min, which was obviously superior to those of [18F]-FDG and L-[ 18F]-FET at all time points. The tumor/brain uptake ratios of [ 18F]3 were 10.36, 17.42, 41.11 at 30 min, 60 min and 120 min post-injection, respectively, and are much higher than those of L-[ 18F] FET (2.54, 2.92 and 2.95) and [18F]-FDG (0.61, 1.02 and 1.33) at the same time points. All these results indicate that [ 18F]3 is promising to become a potential PET tumor imaging agent.
- Chen, Yurong,Feng, Man,Li, Shilei,Xu, Jingli,Ning, Hongyu,He, Yong,Wang, Xiao,Ding, Rui,Qi, Chuanmin
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scheme or table
p. 4745 - 4749
(2012/08/07)
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- Optimization of labeling dipicolylamine derivative, N,N'-(5-(4-aminobutoxy) -1,3-phenylene)bis(methylene)bis(1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl) methanamine), with three 18F-prosthetic groups as potential imaging agents for metastatic infec
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The aim of this study was to develop 18 F-labeled dipicolylamine derivative (compound 1) with three 18 F-prosthetic groups, 18 F-NFP, 18 F-SFB, and 18 F-FET, which were synthesized with labeling yield
- Li, Junling,Gray, Brian D.,Pak, Koon Y,Ng, Chin K.
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experimental part
p. 149 - 154
(2012/08/08)
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- Synthesis and in vitro evaluation of [18F](R)-FEPAQ: A potential PET ligand for VEGFR2
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Synthesis and in vitro evaluation of [18F](R)-N-(4-bromo-2- fluorophenyl)-7-((1-(2-fluoroethyl)piperidin-3-yl)methoxy)-6-methoxyquinazolin- 4-amine ((R)-[18F]FEPAQ or [18F]1), a potential imaging agent for the VEGFR2, usin
- Prabhakaran, Jaya,Arango, Victoria,Majo, Vattoly J.,Simpson, Norman R.,Kassir, Suham A.,Underwood, Mark D.,Polavarapu, Hanish,Bruce, Jeffrey N.,Canoll, Peter,John Mann,Dileep Kumar
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experimental part
p. 5104 - 5107
(2012/09/07)
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