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Radioligand
Kinds of Radioligand Terms modified by Radioligand Selected AbstractsDevelopment of an Efficient and Selective Radioligand for Bradykinin B1 Receptor Occupancy Studies.CHEMINFORM, Issue 16 2005Dai-Shi Su Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: [3H]-M-MPEP, a Potent, Subtype-Selective Radioligand for the Metabotropic Glutamate Receptor Subtype 5.CHEMINFORM, Issue 24 2002Fabrizio Gasparini Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Islet autoimmunity and genetic mutations in Chinese subjects initially thought to have Type 1B diabetesDIABETIC MEDICINE, Issue 1 2006D. Zhang Abstract Aims To explore the contribution of islet autoimmunity and genetic mutations in Chinese patients initially thought to have Type 1B diabetes. Methods A group of 33 Chinese patients with newly diagnosed Type 1B diabetes, were identified by the absence of autoantibodies to glutamic acid decarboxylase (GAD), IA-2, insulin, thyroid globulin or thyroid peroxidase, or high-risk HLA-DQ haplotypes. The cohort was further characterized by measurement of autoantibodies to carboxypeptidase H (CPH) and SOX13 using radioligand assays, and testing for genetic mutations associated with MODY3/MODY6 and mitochondrial diabetes. Mutations of HNF-1, (MODY3) and neuroD1/,2 (MODY6) genes were screened using the single-strand conformation polymorphism (SSCP) technique and sequencing. Mitochondrial DNA mutations were analysed with polymerase chain reaction,restriction fragment length polymorphism (PCR-RFLP). Results Within the cohort, we found one patient with a novel mutation, R321H (CGC,CAC) in exon 5 of the HNF-1, gene, one with ND1 mt3316 G,A mutation in mitochondrial DNA, five with Ala45Thr polymorphisms in the neuroD1/,2 gene, and two patients with autoantibodies to SOX13. Conclusions Some of the Chinese patients originally thought to have Type 1B diabetes do have other evidence of islet autoimmunity and genetic mutations involved in the underlying aetiology. This suggests that more rigorous screening for these conditions is needed before classifying subjects as having Type 1B diabetes. [source] Positron emission tomography and its use to image the occupancy of drug binding sitesDRUG DEVELOPMENT RESEARCH, Issue 2 2003S. John Gatley Abstract The development of positron emission tomography (PET) and the ability to synthesize compounds labeled with the short-lived positron emitters 11C and 18F has made possible the imaging and quantification of drug binding sites in the human body. By conducting PET studies with an appropriate radioligand before and after treatment with a drug, the fraction of the total number of binding sites that is occupied by the drug (the "occupancy" of the site) can often be determined. To the extent that occupancy is a good indicator of pharmacological activity, such PET experiments can aid the development of drug dosage regimens. Some of the general issues involved in PET studies of drug occupancy are discussed. There have been many such studies involving antipsychotic drugs and dopamine D2 receptor radioligands. Since neuroleptics have been extensively reviewed elsewhere, only the major findings are discussed here. Other binding sites (and drug classes) in the dopamine system to which this methodology has been applied include: the dopamine transporter (stimulant drugs) and monoamine oxidase A and B (antidepressant drugs). Occupancy studies are also possible for many drug targets beyond the dopamine system. Drug Dev. Res. 59:194,207, 2003. © 2003 Wiley-Liss, Inc. [source] PET visualization of microglia in multiple sclerosis patients using [11C]PK11195EUROPEAN JOURNAL OF NEUROLOGY, Issue 3 2003J. C. Debruyne Activated microglia are involved in the immune response of multiple sclerosis (MS). The peripheral benzodiazepine receptor (PBR) is expressed on microglia and up-regulated after neuronal injury. [11C]PK11195 is a positron emission tomography (PET) radioligand for the PBR. The objective of the present study was to investigate [11C]PK11195 imaging in MS patients and its additional value over magnetic resonance imaging (MRI) concerning the immuno-pathophysiological process. Seven healthy and 22 MS subjects were included. Semiquantitative [11C]PK11195 uptake values were assessed with normalization on cortical grey matter. Uptake in Gadolinium-lesions was significantly increased compared with normal white matter. Uptake in T2-lesions was generally decreased, suggesting a PBR down-regulation. However, uptake values increased whenever a clinical or MR-relapse was present, suggestive for a dynamic process with a transient PBR up-regulation. During disease progression, an increase of normal-appearing white matter (NAWM) uptake was found, propagating NAWM as the possible real burden of disease. In conclusion, [11C]PK11195 and PET are able to demonstrate inflammatory processes with microglial involvement in MS. [source] Upregulation of [3H]methyllycaconitine binding sites following continuous infusion of nicotine, without changes of ,7 or ,6 subunit mRNA: an autoradiography and in situ hybridization study in rat brainEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2002Manolo Mugnaini Abstract It is well established that exposure of experimental animals to nicotine results in upregulation of the ,4,2-subtype of neuronal nicotinic acetylcholine receptors (nAChRs). The aim of this study was to determine the effect of nicotine on the levels of ,7-nAChRs in rat brain, for which only partial information is available. Rats were infused with nicotine (3 mg/kg/day) or saline for 2 weeks and their brains processed for receptor autoradiography with [3H]methyllycaconitine (MLA), a radioligand with nanomolar affinity for ,7-nAChRs. In control rats binding was high in hippocampus, intermediate in cerebral cortex and hypothalamus, and low in striatum, thalamus and cerebellum. There was high correlation between the distribution of [3H]MLA binding sites and ,7 subunit mRNA (r = 0.816). With respect to saline-treated controls, nicotine-treated rats presented higher [3H]nicotine binding in 11 out of 15 brain regions analysed (average increase 46 ± 6%). In contrast, only four regions showed greater [3H]MLA binding, among which the ventral tegmental area (VTA) and cingulate cortex (mean increase 32 ± 3%). No changes in ,7 mRNA levels were observed after nicotine treatment. Similarly, there was no variation of ,6 subunit transcript in the VTA, a region which may contain MLA-sensitive (non-,7)-,6*-nAChRs (Klink et al., 2001). In conclusion, nicotine increased [3H]MLA binding, although to a smaller extent and in a more restricted regional pattern than [3H]nicotine. The enhancement of binding was not paralleled by a significant change of ,7 and ,6 subunit transcription. Finally, the present results provide the first anatomical description of the distribution of [3H]MLA binding sites in rat brain. [source] Brain region binding of the D2/3 agonist [11C]-(+)-PHNO and the D2/3 antagonist [11C]raclopride in healthy humansHUMAN BRAIN MAPPING, Issue 4 2008Ariel Graff-Guerrero Abstract The D2 receptors exist in either the high- or low-affinity state with respect to agonists, and while agonists bind preferentially to the high-affinity state, antagonists do not distinguish between the two states. [11C]-(+)-PHNO is a PET D2agonist radioligand and therefore provides a preferential measure of the D2high receptors. In contrast, [11C]raclopride is an antagonist radioligand and thus binds with equal affinity to the D2 high- and low-affinity states. The aim was to compare the brain uptake, distribution and binding characteristics between [11C]-(+)-PHNO and [11C]raclopride in volunteers using a within-subject design. Both radioligands accumulated in brain areas rich in D2/D3 -receptors. However, [11C]-(+)-PHNO showed preferential uptake in the ventral striatum and globus pallidus, while [11C]raclopride showed preferential uptake in the dorsal striatum. Mean binding potentials were higher in the putamen (4.3 vs. 2.8) and caudate (3.4 vs 2.1) for [11C]raclopride, equal in the ventral-striatum (3.4 vs. 3.3), and higher in the globus pallidus for [11C]-(+)-PHNO (1.8 vs. 3.3). Moreover [11C]-(+)-PHNO kinetics in the globus pallidus showed a slower washout than other regions. One explanation for the preferential binding of [11C]-(+)-PHNO in the globus pallidus and ventral-striatum could be the presence of a greater proportion of high- vs. low-affinity receptors in these areas. Alternatively, the observed distribution could also be explained by a preferential binding of D3 -over-D2 with [11C]-(+)-PHNO. This differential binding of agonist vs. antagonist radioligand, especially in the critically important region of the limbic striatum/pallidum, offers new avenues to investigate the role of the dopamine system in health and disease. Hum Brain Mapp 2008. © 2007 Wiley-Liss, Inc. [source] Use of [125I]4,-iodoflavone as a tool to characterize ligand-dependent differences in Ah receptor behaviorJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 6 2002Hollie I. Swanson Abstract We have synthesized [125I]4,-iodoflavone to study Ah receptor (AhR),ligand interactions by a class of AhR ligands distinct from the prototypic ligand 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). This radioligand allows the comparison of AhR,ligand interactions using a ligand that differs in AhR affinity, and yet has the same radiospecific activity as [125I]2-iodo-7,8-dibromodibenzo- p -dioxin. Specific binding of [125I]4,-iodoflavone with the AhR was detected as a single radioactive peak (,9.7 S) following density sucrose gradient analysis. Cytosolic extracts from both Hepa 1 and HeLa cells were used as the source of mouse and human AhR, respectively. A ,6.7 S form of radioligand-bound Ah receptor was detected in the high salt nuclear extracts of both cell lines. In HeLa cells approximately twofold more [125I]4,-iodoflavone,AhR 6 S complex, compared with [125I]2-iodo-7,8-dibromodibenzo- p -dioxin, was recovered in nuclear extracts. A comparison of the ability of 4,-iodoflavone and TCDD to cause time-dependent translocation of AhR-yellow fluorescent protein revealed that 4,-iodoflavone was more efficient at enhancing nuclear accumulation of the receptor. These results suggest that [125I]4,-iodoflavone is a particularly useful and easily synthesized ligand for studying the AhR. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:298,310, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10053 [source] Development of liver dysfunction after delivery is possibly due to postpartum autoimmune hepatitis.JOURNAL OF INTERNAL MEDICINE, Issue 4 2002A report of three cases Autoimmune diseases, especially autoimmune thyroid disease, frequently develop after delivery due to the immune rebound mechanism. Most cases involve transient dysfunction of affected organs. Weexamined three patients who developed liver dysfunction after delivery. They were all diagnosed with definite or probable autoimmune hepatitis using the scoring system of the International Autoimmune Hepatitis Group. Moreover, all of them had anti-CYP2D6 antibodies detected by a sensitive radioligand assay. Our findings strongly suggest that liver dysfunction is induced by postpartum autoimmune hepatitis, and clinicians should be aware of this disease. [source] Preparation and biodistribution of [125I]Melphalan: a potential radioligand for diagnostic and therapeutic applicationsJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 1 2010A. M. Amin Abstract This paper addresses the development of a new radiopharmaceutical for cancer imaging and therapy. The optimization of the labeling conditions of thymidine analogue, melphalan, with125I is described. High radiochemical yield 96.8% was obtained by reacting 0.2,mg melphalan with 125I in the presence of choloramin-T as oxidizing agent in 0.5,M phosphate buffer, pH 7, at 70°C for 15,min. Preliminary in vivo study was done in non-tumor bearing mice. The results revealed that this new tracer,125I-melphalan, has a high affinity to be localized in the tumor site for a long period, which indicates the specificity of this tracer to the tumor cells. The labeled compound was cleared quickly from most of the body organs. These findings suggest that 125I-melphalan allows imaging and treatment of cancer. 125I-melphalan meets most of the requirements necessary to be used as a successful diagnostic and therapeutic agent: it is a low-molecular-weight molecule that diffuses readily in the tissues, and dose not induce an antibody response. Copyright © 2009 John Wiley & Sons, Ltd. [source] Preparation and in vitro evaluation of 99mTc-labelled bovine lactadherin as a novel radioligand for apoptosis detectionJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 4 2007Lasse N. Waehrens Abstract Lactadherin is an opsonin, which binds with high affinity to phosphatidylserine exposed on the surface of apoptotic cells via its C1C2 domains. Phagocytosis of the apoptotic cells is then facilitated by an Arg-Gly-Asp (RGD)- mediated binding to macrophages surface integrins. The present report describes the synthesis of 99mTc-HYNIC,lactadherin with a radiochemical yield of 88±5% (n= 3) and a specific activity of 41±5 µCi/µg (n=3) when purified. Purified 99mTc-HYNIC,lactadherin was shown to be stable for at least 5 h when supplemented with 1.5 mg/ml fatty-acid-free BSA. The radiolabelled protein retained its phospholipid binding ability that was verified by its ability to bind to apoptotic HL60 leukaemia cells. The apoptotic cells demonstrated a RGD independent 3- to 4-fold excess binding of the radioactive component relative to control cells. Surplus of unlabelled lactadherin almost completely inhibited the binding of 99mTc-HYNIC,lactadherin. Collectively our data indicate that 99mTc-HYNIC,lactadherin is potentially useful as a new molecular binding tool for the identification of apoptotic cells. Copyright © 2007 John Wiley & Sons, Ltd. [source] Radiosynthesis of 2- exo -(2,-[18F]Fluoro-3,-(4-fluorophenyl)-pyridin-5,-yl)-7-azabicyclo[2.2.1]heptane ([18F]F2PhEP), a potent epibatidine-based radioligand for nicotinic acetylcholine receptor PET imagingJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 6 2006Gaëlle Roger Abstract 2- exo -(2,-Fluoro-3,-(4-fluorophenyl)-pyridin-5,-yl)-7-azabicyclo[2.2.1]heptane (F2PhEP), a novel, epibatidine-based, ,4,2-selective nicotinic acetylcholine receptor antagonist of low toxicity, as well as the corresponding N- Boc-protected chloro- and bromo derivatives as precursors for labelling with fluorine-18 were synthesized from 7- tert -butoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene in 13, 19 and 8% overall yield, respectively. [18F]F2PhEP was prepared in 8,9% overall yield (non-decay-corrected) using 1 mg of the bromo derivative in the following two-step radiochemical process: (1) no-carrier-added nucleophilic heteroaromatic ortho- radiofluorination with the activated K[18F]F-Kryptofix®222 complex in DMSO using microwave activation at 250 W for 90 s, followed by (2) quantitative TFA-induced removal of the N -Boc protective group. Radiochemically pure (>95%) [18F]F2PhEP (1.48,1.66 GBq, 74,148 GBq/µmol) was obtained after semi-preparative HPLC (Symmetry® C18, eluent aqueous 0.05 M NaH2PO4 CH3CN: 78/22 (v:v)) in 75,80 min starting from an 18.5 GBq aliquot of a cyclotron-produced [18F]fluoride production batch. Copyright © 2006 John Wiley & Sons, Ltd. [source] Automated radiosynthesis of [18F]SPA-RQ for imaging human brain NK1 receptors with PETJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 1 2006Frederick T. Chin Abstract [18F]SPA-RQ is an effective radioligand for imaging brain neurokinin type-1 (NK1) receptors in clinical research and drug discovery with positron emission tomography. For the automated regular production of [18F]SPA-RQ for clinical use in the USA under an IND we chose to use a modified commercial synthesis module (TRACERlab FXF-N; GE Medical Systems) with an auxiliary custom-made robotic cooling,heating reactor, after evaluating several alternative radiosynthesis conditions. The automated radiosynthesis and its quality control are described here. [18F]SPA-RQ was regularly obtained within 150 min from the start of radiosynthesis in high radiochemical purity (>99%) and chemical purity and with an overall decay-corrected radiochemical yield of 15±2% (mean±S.D.; n=10) from cyclotron-produced [18F]fluoride ion. The specific radioactivity of [18F]SPA-RQ at the end of synthesis ranged from 644 to 2140 mCi/µmol (23.8,79.2 GBq/µmol). Copyright © 2005 John Wiley & Sons, Ltd. [source] Use of LC,MS,MS for the rapid, specific and sensitive quality control measurement of carrier in a PET radioligand: [18F]FECNTJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 13 2005H. Umesha Shetty Abstract In the production of radioligands for imaging low concentrations of target proteins (e.g. receptors or transporters) in human subjects with positron emission tomography, control of specific radioactivity is necessary for efficacy and safety. Such quality control requires a fast method to be available for measuring carrier (non-radioactive ligand) in each batch of radioligand, preceding its release for administration. Measurement is usually achieved with HPLC equipped with an ultraviolet (UV) absorbance detector. However, this method is not easily applicable to radioligands that have low UV extinction coefficients and are produced at high specific radioactivity, such as [18F] (2,-carbomethoxy-3,-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane; [18F]FECNT). Here we describe a fast, specific and sensitive LC,MS,MS method for measuring carrier in [18F]FECNT preparations. Small samples of formulated [18F]FECNT plus an added internal standard (2,-carbomethoxy-3,-(4-chlorophenyl)-8-(n -propyl)nortropane; INTSTD) are rapidly eluted from a short reverse phase HPLC column into an MS probe. Following electrospray ionization, the molecular ions ([MH]+) of FECNT (m/z=326) and INTSTD (m/z=322) are isolated and energized for collision-induced dissociation. The product ions from FECNT (m/z=294) and INTSTD (m/z=290) are monitored selectively. The calibration curve for MS response is linear for FECNT concentrations in the range 2,20 pg/µl and suitable for reproducibly (RSD 5%) and rapidly (<3 min) measuring low concentrations of carrier in [18F]FECNT preparations. Copyright © 2005 John Wiley & Sons, Ltd. [source] Synthesis of (R)- and (S)-[O-methyl - 11C]N -[2-[3-(2-cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]- N,-(4-methoxy-phenyl)-urea as candidate high affinity ,1 -adrenoceptor PET radioligandsJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 10 2005Stefan Wagner Abstract Molecular imaging and quantification of myocardial ,1 -adrenoceptor (AR) rather than total , -AR density is of great clinical interest since cardiac biopsy studies suggest that myocardial ,1 -AR density is reduced in patients with chronic heart failure whereas cardiac ,2 -AR density may vary. Positron emission tomography (PET), with appropriate radioligands, offers the possibility to assess , -AR density non-invasively in humans. However, no PET radioligand for the selective imaging of cardiac ,1 -ARs is clinically available. Here some derivatives of the well characterized ,1 -AR selective antagonist, ICI 89,406, namely the enantiomers of N -[2-[3-(2-cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]- N,-(4-hydroxy-phenyl)-urea (5a and 5b) were synthesized and evaluated in vitro. The (R)-isomer 5a was more ,1 -selective but has lower affinity than its (S)-enantiomer 5b (,1 -AR selectivity: 6100 vs 1240; ,1 -affinity: K1 = 0.288 nM vs K1 = 0.067 nM). Etherification of the analogous desmethyl precursors, 5e and 5f, respectively, with [11C]iodomethane gave 11C-labelled versions of 5a and 5b, namely 5g and 5h, in 44 ± 5% radiochemical yield (decay-corrected) and 97.4 ± 1.3% radiochemical purity with specific radioactivities of 26.4 ± 9.4 GBq/µmol within 41.2 ± 3.4 min from the end of bombardment (n = 14). 5g and 5h are now being evaluated as candidate radioligands for myocardial ,1 -ARs. Copyright © 2005 John Wiley & Sons, Ltd. [source] Radiosyntheses and reactivities of novel [18F]2-fluoroethyl arylsulfonatesJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 10 2005John L. Musachio Abstract [18F]2-Fluoroethyl tosylate ([18F]FEOX, X=Ts) is widely used for labeling radiotracers for positron emission tomography (PET). Little work has been reported on syntheses of other [18F]2-fluoroethyl arylsulfonates ([18F]FEOX) that bear a less electron-rich aryl group, even though these might offer enhanced reactivities. Thus, a series of novel [18F]FEOX (X=benzenesulfonyl, brosyl, nosyl, 3,4-dibromobenzenesulfonyl) were synthesized and reactivities compared to [18F]FEOTs. Precursors for radiolabeling (bis -ethylene glycol arylsulfonates) and reference FEOX were synthesized (alcohol+arylsulfonyl chloride+KOSiMe3 in THF). Regardless of substitution pattern, [18F]FEOX (110°C, 5 min, acetonitrile) were obtained in similar decay-corrected isolated radiochemical yields (RCY; 47,53%). All [18F]FEOX gave excellent RCYs (64,87%) of the dopamine uptake radioligand, [18F]FECNT (130°C, 10 min, acetonitrile). The 3,4-dibromobenzensulfonate gave the highest RCY of [18F]FECNT (87%) and this HPLC-purified labeling agent was used directly for efficient [18F]FECNT production. When the secondary aniline of an amyloid probe (HM-IMPY) or p -nitrophenol was reacted with [18F]FEOX, RCYs were appreciably higher for brosylate and nosylate than for tosylate, while 3,4-dibromobenzenesulfonate again gave the highest RCY. Owing to the high reactivity of the new [18F]FEOX and their ease of syntheses via stable precursors, such agents (particularly 3,4-dibromobenzenesulfonate) should be considered as alternatives to [18F]FEOTs. Copyright © 2005 John Wiley & Sons, Ltd. [source] Radiosynthesis and in vivo evaluation of [11C]Ro-647312: a novel NR1/2B subtype selective NMDA receptor radioligandJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 13 2004Frédéric Dollé Abstract [2-(3,4-Dihydro-1H-isoquinolin-2-yl)-pyridin-4-yl]-dimethylamine, Ro-647312 (1) represents a new novel class of NR1/2B subtype selective NMDA ligand. Ro-647312 has been radiolabelled with carbon-11 using [11C]methyl triflate from the nor- methyl compound 2. The reaction was performed in acetone as solvent using aqueous NaOH as base. Following HPLC purification [11C]Ro-647312 ([11C]- 1) was obtained in 6.9,9.2% (n = 3) radiochemical yield decay-corrected based on starting [11C]CO2, with specific radioactivity measured at the end of the radiosynthesis ranging from 1.0 to 3.5 Ci/µmol (37,129 GBq/µmol). Radiochemical and chemical purities were assessed as >99 and >95%, respectively. Following i.v. injection of [11C]- 1 in rat, the distribution of radioactivity was homogeneous in all brain structures and did not correlate with the known distribution of NR2B subunits. The radioactivity observed in plasma was also higher than any brain structure throughout the time course of the experiment. [11C]- 1 does not possess the required properties for imaging NMDA receptors using positron emission tomography. Copyright © 2004 John Wiley & Sons, Ltd. [source] Synthesis and preliminary in vivo evaluation of 4-[18F]fluoro- N -{2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethyl}benzamide, a potential PET radioligand for the 5-HT1A receptorJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 9 2004M. Vandecapelle Abstract 4-Fluoro- N -{2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethyl}benzamide is a full 5-HT1A agonist with high affinity (pKi=9.3), selectivity and a c log P of 3.045. The corresponding PET radioligand 4-[18F]fluoro- N -{2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethyl}benzamide was synthesized by nucleophilic aromatic substitution on the nitro precursor. The fluorinating agent K[18F]F/Kryptofix 2.2.2 was both dried (9 min, 700 W) and incorporated in the precursor (5 min, 700 W) using a commercially available microwave oven. In a total synthesis time of 60 min, an overall radiochemical yield of 18% (SD=5, n=7, EOS) was obtained. Radiochemical purity was always higher than 99% and specific activity always higher than 81.4 GBq/µmol (2.2 Ci/µmol). Initial brain uptake in mice was 2.19% ID (5.47% ID/g, 2 min) but decreased rapidly (0.17% ID, 0.45% ID/g (60 min)). During the first 20 min p.i., radioactivity concentration of the brain was significantly higher than that of blood demonstrating good brain entry of the tracer. Copyright © 2004 John Wiley & Sons, Ltd. [source] Synthesis of [18F]3-[1-(3-fluoropropyl)-(S)-pyrrolidin-2-ylmethoxy]pyridine ([18F]NicFP): a potential ,4,2 nicotinic acetylcholine receptor radioligand for PETJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 14 2003Filip Dumont Abstract Nicotinic acetylcholine receptors are widely distributed throughout the human brain and are believed to play a role in several neurological and psychiatric disorders. In order to identify an effective PET radioligand for in vivo assessment of the ,4,2 subtype of nicotinic receptor, we synthesized [18F]3-[1-(3-fluoropropyl)-(S)-pyrrolidin-2-ylmethoxy]pyridine (NicFP). The in vitro KD of NicFP was determined to be 1.1 nM, and the log P value obtained by HPLC analysis of the unlabelled standard was found to be 2.2. The radiosynthesis of [18F]NicFP was carried out by a nucleophilic substitution reaction of anhydrous [18F]fluoride and the corresponding mesylate precursor. After purification by HPLC, the radiochemical yield was determined to be 11.3±2.1% and the specific activity was 0.47±0.18 Ci/,mol (EOS, n = 3). The time of synthesis and purification was 99±2 min. The final product was prepared as a sterile saline solution suitable for in vivo use. Copyright © 2003 John Wiley & Sons, Ltd. [source] Synthesis and evaluation of tritium labelled 10-methylgalanthamine iodide: a novel compound to examine the mechanism of interaction of galanthamine derivatives with the nicotinic acetylcholine receptorsJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 12 2003Andreas Schildan Abstract A new promising galanthamine derivative, 10-[3H]methylgalanthamine iodide, was synthesized for binding studies to nicotinic acetylcholine receptors expressed in Torpedo electric ray electroplaques. Galanthamine was reacted with [3H]methyl iodide to yield 10-[3H]methylgalanthamine iodide with a radiochemical yield of >70% and a specific activity of 32 Ci/mmol after purification via solid phase extraction. To test the ligand properties of the radioligand, calcium imaging and electrophysiology of the non-radioactive analogue were performed to obtain an EC50 of 270 nM, a Hill coefficient of 1.9 and the induced cell current. Copyright © 2003 John Wiley & Sons, Ltd. [source] A non-peptide radioiodinated high affinity melanocortin-4 receptor ligandJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 11 2003Felikss Mutulis Abstract 4-Cyclohexyl-4-[(1,2,4-triazol-1-yl)methyl]piperidine was introduced into stepwise peptide synthesis procedures using Boc chemistry and derivatives of D -4-iodophenylalanine and D -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. A halogen replacement analogue (I-Mex2) of a known high affinity melanocortin-4 receptor selective compound resulted. It showed a subnanomolar affinity when evaluated on the melanocortin-4 receptor in competition with the , -MSH peptide analogue 125I-NDP-MSH. By treatment with hexamethylditin and tetrakis(triphenylphosphine) palladium I-Mex2 was converted to the corresponding trimethylstannyl derivative. In the next step, Na125I was oxidized by an iodobead. Iododestannylation proceeded in the presence of 1 M phosphate buffer, pH 2.5, and the radio-active derivative 125I-Mex2 formed was separated by HPLC at 40% radiochemical yield. Preliminary investigation showed that 125I-Mex2 is useful as a radioligand for melanocortin-4 receptor binding studies. Copyright © 2003 John Wiley & Sons, Ltd. [source] Efficient synthesis of [11C]befloxatone, a selective radioligand for the in vivo imaging of MAO-A density using PETJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 9 2003F. Dollé Abstract Carbon-11 labelled befloxatone ((5R)-5-(methoxymethyl)-3-[4-[(3R)-4,4,4-trifluoro-3-hydroxybutoxy]phenyl]-2-oxazolidinone) is a reversible and selective monoamine oxidase-A (MAO-A) inhibitor and appears to be a new potent PET tracer for the in vivo imaging of MAO-A density. In this paper, the radiosynthesis of befloxatone was investigated and orientated towards the preparation of multi milliCuries of radiotracer. Typically, using no-carrier-added [11C]phosgene, 150,300 mCi (5.55,11.10 GBq) of [11C]befloxatone was obtained within 20 min of radiosynthesis (including HPLC purification) with specific radioactivities ranging from 500 to 2000 mCi/µmol (18.5,74.0 GBq/µmol). The high efficiency of these radiosyntheses allows for multi-injection protocols and kinetic approaches for absolute quantification of the tracer. Copyright © 2003 John Wiley & Sons, Ltd. [source] Ortho -[18F]Fluoronitrobenzenes by no-carrier-added nucleophilic aromatic substitution with K[18F]F,K222,A comparative studyJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 13 2002M. Karramkam Abstract The scope of the nucleophilic aromatic ortho -fluorinations from the corresponding ortho -halonitrobenzene precursors (halo-to-fluoro substitutions) with no-carrier-added [18F]fluoride ion as its activated K[18F]F,K222 complex has been evaluated via the radiosynthesis of ortho -[18F]fluoronitrobenzene, chosen as a model reaction. The parameters studied include the influence of the leaving group in the ortho position of the phenyl ring (,Cl, ,Br, ,l), the quantity of precursor used, the type of activation (conventional heating or microwave irradiations), the solvent, the temperature and the reaction time. The iodo-precursor was completely unreactive and the bromo-precursor gave only low incorporation (<10%) in the optimal conditions used (conventional heating at 145°C or microwave activation, 100 W for 120 s). Only the chloro-precursor was found reactive in the conditions described above and up to 70% yield was observed for the formation of ortho -[18F]fluoronitrobenzene ([18F]- 1). In all the experiments, the unwanted ortho -[18F]fluoro-halobenzenes, potentially resulting from the nitro-to-fluoro substitution, could not be detected. These results will be applied for the radiosynthesis of 5-[18F]fluoro-6-nitroquipazine, a potent radioligand for the imaging of the serotonin transporter with PET. Copyright © 2002 John Wiley & Sons, Ltd. [source] Efficient synthesis and formulation of (R)-(,)-[11C]Deprenyl, a selective radioligand for the quantification of MAO-B activity using PETJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 10 2002Frédéric Dolle Abstract Carbon-11 labeled (R)-(,)-Deprenyl is the tracer of reference for the quantification of monoamine oxidase (MAO)-B activity with PET. In this paper, its radiosynthesis is re-investigated and oriented towards the preparation of multi-milliCuries of radiotracer. Typically, using no-carrier-added [11C]methyl triflate as the alkylating agent, 140,190 mCi (5.1,7.0 GBq) of (R)-(,)-[11C]Deprenyl was obtained within 30 min of radiosynthesis (including HPLC purification and formulation) with specific radioactivities ranging from 0.8 to 1.2 Ci/,mol (29.6,44.4 GBq/,mol). The high efficiency of these radiosyntheses allows for multi-injection protocols and kinetic approaches for absolute quantification of the tracer. Copyright © 2002 John Wiley & Sons, Ltd. [source] Precursor synthesis and radiolabelling of [11C]ADAM: a potential radioligand for the serotonin transporter exploration by PETJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 2 2001Johnny VERCOUILLIE Abstract The serotoninergic system is involved in a variety of neurological and psychiatric disorders. Exploration of the serotonin transporters (5-HTT) in living human brain by PET would be of great value for better understanding, diagnosis and therapeutic follow up of these diseases. In order to obtain a selective radioligand to explore the 5-HTT by PET we report the synthesis of [11C]N,N-dimethyl-2-(2-amino-4-iodophenylthio)-benzylamine ([11C]ADAM). The precursor for labelling N-demethyl ADAM, was obtained in five steps using 2,5-dibromonitrobenzene and 2-thio-N-methylbenzamide as starting material. [11C]ADAM was synthesised by N-alkylation of the precursor using [11C]methyl iodide in DMF. The incorporation yield of [11C]methyl iodide was in the range of 50 to 70%. Finally [11C]ADAM was obtained in 30 minutes synthesis time including HPLC and with a radiochemical purity better than 99%. Copyright © 2001 John Wiley & Sons, Ltd. [source] Binding characteristics and sensitivity to endogenous dopamine of [11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity state of D2 receptors in vivo using positron emission tomographyJOURNAL OF NEUROCHEMISTRY, Issue 4 2006Nathalie Ginovart Abstract [11C]-(+)-PHNO (4-propyl-9-hydroxynaphthoxazine) is a new agonist radioligand that provides a unique opportunity to measure the high-affinity states of the D2 receptors (D2 -high) using positron emission tomography (PET). Here we report on the distribution, displaceablity, specificity and modeling of [11C]-(+)-PHNO and compare it with the well characterized antagonist D2 radioligand, [11C]raclopride, in cat. [11C]-(+)-PHNO displayed high uptake in striatum with a mean striatal binding potential (BP) of 3.95 ± 0.85. Pre-treatment with specific D1 (SCH23390), D2 (raclopride, haloperidol) and D3 receptor (SB-277011) antagonists indicated that [11C]-(+)-PHNO binding in striatum is specific to D2 receptors. Within-subject comparisons showed that [11C]-(+)-PHNO BP in striatum was almost 2.5-fold higher than that measured with [11C]-(,)-NPA ([11C]-(,)-N-propyl-norapomorphine). Comparison of the dose-effect of amphetamine (0.1, 0.5 and 2 mg/kg; i.v.) showed that [11C]-(+)-PHNO was more sensitive to the dopamine releasing effect of amphetamine than [11C]raclopride. Amphetamine induced up to 83 ± 4% inhibition of [11C]-(+)-PHNO BP and only up to 56 ± 8% inhibition of [11C]raclopride BP. Scatchard analyses of [11C]-(+)-PHNO and [11C]raclopride bindings in two cats showed that the Bmax obtained with the agonist (29.6 and 32.9 pmol/mL) equalled that obtained with the antagonist (30.6 and 33.4 pmol/mL). The high penetration of [11C]-(+)-PHNO in brain, its high signal-to-noise ratio, its favorable in vivo kinetics and its high sensitivity to amphetamine shows that [11C]-(+)-PHNO has highly suitable characteristics for probing the D2 -high with PET. [source] Elevated serotonin transporter binding in depressed patients with Parkinson's disease: A preliminary PET study with [11C]DASB,MOVEMENT DISORDERS, Issue 12 2008Isabelle Boileau PhD Abstract This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early-stage PD patients and in seven healthy matched-control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [11C]DASB. Depressed PD patients displayed a wide-spread increase (8,68%) in [11C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [11C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[11C]DASB findings in major depression, the present preliminary data suggest that increased [11C]DASB binding, possibly reflecting greater serotonin transporter density (up-regulation), might be a pathological feature of depression in Parkinson's disease,and possibly a characteristic of depressive illness in general. © 2008 Movement Disorder Society [source] Antinociceptive Synergism of MD-354 and Clonidine.BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2010Part II. In the present investigation, a possible role for ,2 -adrenoceptors was examined. Mechanistic studies using yohimbine (a subtype non-selective ,2 -adrenoceptor antagonist), BRL 44408 (a preferential ,2A -adrenoceptor antagonist) and imiloxan (a preferential ,2B/C -adrenoceptor antagonist) on the antinociceptive actions of a MD-354/clonidine combination were conducted. Subcutaneous pre-treatment with all three antagonists inhibited the antinociceptive synergism of MD-354 and clonidine in the mouse tail-flick assay in a dose-dependent manner (AD50 = 0.33, 2.1, and 0.17 mg/kg, respectively). Enhancement of clonidine antinociception by MD-354 did not potentiate clonidine's locomotor suppressant activity in a mouse locomotor assay. When [ethyl- 3H]RS-79948-197 was used as radioligand, MD-354 displayed almost equal affinity to ,2A - and ,2B -adrenoceptors (Ki = 110 and 220 nM) and showed lower affinity at ,2C -adrenoceptors (Ki = 4,700 nM). MD-354 had no subtype-selectivity for the ,2 -adrenoceptor subtypes as an antagonist in functional [35S]GTP,S binding assays. MD-354 was a weak partial agonist at ,2A -adrenoceptors. Overall, in addition to the 5-HT3 receptor component, the present investigation found MD-354 to be a weak partial ,2A -adrenoceptor agonist that enhances clonidine's thermal antinociceptive actions through an ,2 -adrenoceptor-mediated mechanism without augmenting sedation. [source] [3H] Citalopram Binding to Serotonin Transporter Sites in Minnow BrainsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2007Georgianna G. Gould Herein, we examined whether golden shiner (Notemigonus crysoleucas) or fathead minnow (Pimphales promelas) SERTs and catecholamine transporters respond comparably to mammalian SERTs and NETs. We compared the pharmacological profiles of central SERT and NET binding sites of the golden shiner minnow to those of rats. Homogenate binding with the radioligand [3H] citalopram indicated that golden shiner SERT has a KD of 7 ± 3 nM and a Bmax of 226 ± 46 fmol/mg protein. These values are similar to those of rat cortical SERT (KD 1.4 ± 0.1 nM and Bmax 240 ± 48 fmol/mg protein). We also examined SERT binding in fathead minnow brain, and found it similar to that of the golden shiner. A putative golden shiner NET, measured using [3H] nisoxetine, had KD = 12 ± 5 nM and Bmax = 187 ± 49 fmol/mg protein, whereas rat hippocampal NET had KD = 5 ± 2 nM and Bmax = 93 ± 8 fmol/mg protein. Minnow SERT and NET binding is displaceable by selective reuptake inhibitors. Finally, we exposed zebrafish (Danio rerio) to the serotonin reuptake inhibiting antidepressant sertraline or the organophosphate chlorpyrifos for 21 days. After either treatment, SERT binding was reduced by 50% (n = 3,6, P < 0.05). In summary, minnow central SERT and NET express slightly lower affinity for antidepressants than rats. However, magnitudes of affinity are similar, and minnow SERT binding is decreased by chronic sertraline or chlorpyrifos administration. [source] Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorderBIPOLAR DISORDERS, Issue 4 2003E Scarr Objectives:, The purpose of this study was to determine whether there are changes in the density of ionotropic glutamate receptors in the hippocampus of subjects with bipolar disorder. Methods:, Using in situ radioligand binding with semiquantitative autoradiography, we measured the density of [3H]MK-801, [3H]CGP39653, [3H]AMPA and [3H]kainate binding in hippocampi, obtained postmortem, from eight subjects with type 1 bipolar disorder and 8 age- and sex-matched controls. Results:, In subjects with bipolar disorder there were significant decreases in the density of [3H]MK-801 binding in the Cornu Ammonis (CA) 3 (mean ± SEM; 108.8 ± 12.2 versus 166.2 ± 18.0 fmol/mg ETE, p < 0.005) as well as the pyramidal (102.8 ± 9.2 versus 136.6 ± 11.2 fmol/mg ETE, p < 0.05) and polymorphic (21.73 ± 6.5 versus 53.26 ± 11.6 fmol/mg ETE, p < 0.05) layers of the subiculum. In addition, two-way analysis of variance (ANOVA) revealed a decrease in the density of [3H]CGP39653 binding across the hippocampal formation in bipolar subjects, which did not reach significance in any subregion. There were no changes in the densities of [3H]AMPA or [3H]kainate binding in these subjects. Conclusions:, [3H]CGP39653 and [3H]MK-801 bind to the glutamate binding site and open ion channel of the n -methyl- d -aspartate (NMDA) receptor, respectively. Therefore, these data suggest that there is a decrease in the number of open ion channels associated with no significant change in the apparent density of NMDA receptors in regions of the hippocampus from subjects with bipolar disorder. [source] | ||||||||||||||||