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Anton Forsberg,
Anders Juréus,
Zsolt Cselényi,
Maria Eriksdotter,
Yvonne Freund-Levi,
Fredrik Jeppsson,
Britt-Marie Swahn, Johan Sandell,
Per Julin,
Magnus Schou,
Jan Andersson,
Peter Johnström,
Katarina Varnäs,
Christer Halldin,
Lars Farde,
Samuel Svensson
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ABSTRACT: PURPOSE: The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer's disease (AD). METHODS: In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [(11)C]AZD2995 and [(11)C]AZD2184 in three healthy control subjects and seven AD patients. RESULTS: AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [(3)H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [(11)C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [(11)C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus. CONCLUSION: Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [(11)C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [(11)C]AZD2995. However, the very low nonspecific binding of [(11)C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.
European Journal of Nuclear Medicine 01/2013; · 4.53 Impact Factor
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ABSTRACT: The synthesis and SAR of new β-amyloid binding agents are reported. Evaluation of important properties for achieving good signal-to-background ratio is described. Compounds 27, 33, and 36 displayed desirable lipophilic and pharmacokinetic properties. Compound 27 was further evaluated with autoradiographic studies in vitro on human brain tissue and in vivo in Tg2576 mice. Compound 27 showed an increased signal-to-background ratio compared to flutemetamol 4, indicating its suitability as PET ligand for β-amyloid deposits in AD patients. The preparation of the corresponding (18)F-labeled PET radioligand of compound 27 is presented.
Bioorganic & medicinal chemistry letters 05/2012; 22(13):4332-7. · 2.65 Impact Factor
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ABSTRACT: Positron emission tomography (PET) radioligands that bind selectively to beta-amyloid plaques (Abeta) are promising imaging tools aimed at supporting the diagnosis of Alzheimer's disease and the evaluation of new drugs aiming to modify amyloid plaque load. For extended clinical use, there is a particular need for PET tracers labeled with fluorine-18, a radionuclide with 110 min half-life allowing for central synthesis followed by wide distribution. The development of fluorinated radioligands is, however, challenging because of the lipophilic nature of aromatic fluorine, rendering fluorinated ligands more prone to have high non-specific white matter binding. We have here developed the new benzofuran-derived radioligand containing fluorine, AZD4694 that shows high affinity for beta-amyloid fibrils in vitro (K(d) = 2.3 +/- 0.3 nM). In cortical sections from human Alzheimer's disease brain [(3)H]AZD4694 selectively labeled beta-amyloid deposits in gray matter, whereas there was a lower level of non-displaceable binding in plaque devoid white matter. Administration of unlabeled AZD4694 to rat showed that it has a pharmacokinetic profile consistent with good PET radioligands, i.e., it quickly entered and rapidly cleared from normal rat brain tissue. Ex vivo binding data in aged Tg2576 mice after intravenous administration of [(3)H]AZD4694 showed selective binding to beta-amyloid deposits in a reversible manner. In Tg2576 mice, plaque bound [(3)H]AZD4694 could still be detected 80 min after i.v. administration. Taken together, the preclinical profile of AZD4694 suggests that fluorine-18 labeled AZD4694 may have potential for PET-visualization of cerebral beta-amyloid deposits in the living human brain.
Journal of Neurochemistry 08/2010; 114(3):784-94. · 4.06 Impact Factor
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Britt-Marie Swahn,
David Wensbo, Johan Sandell,
Daniel Sohn,
Can Slivo,
David Pyring,
Jonas Malmström,
Erwan Arzel,
Michaela Vallin,
Margareta Bergh,
Fredrik Jeppsson,
Allan E Johnson,
Anders Juréus,
Jan Neelissen,
Samuel Svensson
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ABSTRACT: The syntheses and SAR of new series of beta-amyloid binding agents are reported. The effort to optimize signal-to-background ratios for these ligands are described. Compounds 8, 21 and 30 displayed desirable lipophilicity and pharmacokinetic properties. Compounds 8 and 21 were evaluated with in vitro autoradiographic studies and in vivo in APP/PS1 transgenic mice. It is shown that it was possible to increase the signal-to-background ratios compared to PIB 1, as demonstrated by compounds 8 and 21.
Bioorganic & medicinal chemistry letters 01/2010; 20(6):1976-80. · 2.65 Impact Factor
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ABSTRACT: The presence of beta-amyloid plaques in brain is a hallmark of Alzheimer's disease (AD) and serves as a biomarker for confirmation of diagnosis postmortem. Positron emission tomography (PET) radioligands such as Pittsburgh compound B ([(11)C]-2-(3-fluoro-4-methylamino-phenyl)-benzothiazol-6-ol) (PIB) binds selectively to beta-amyloid and are promising new tools supporting the clinical diagnoses of AD. In addition, such methodology may be useful for evaluation of new drugs aiming at reduction of amyloid plaque load. The objective of this study is to develop a new amyloid selective PET radioligand with higher signal-to-background ratio when compared with existing amyloid PET ligands. The lead compound, AZD2184, (2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol) was found to have high affinity for amyloid fibrils in vitro (K(d): 8.4 +/- 1.0 nM). Two minutes after i.v. administration in rats, about 1% of the dose was in brain. In vitro autoradiography on cortical brain sections from amyloid-beta precursor protein/presenilin 1 (APP/PS1) mice and AD patients showed that while [(3)H]AZD2184 and [(3)H]PIB are mutually displaceable, [(3)H]AZD2184 displays a higher signal-to-background ratio primarily by virtue of lower background binding levels. The ratio of binding ability in prefrontal cortex (high plaque load) to subcortical white matter (background) was 4.5 for [(3)H]AZD2184 and 0.8 for [(3)H]PIB at 1 nM. In adjacent cortical sections from APP/PS1 mouse as well as from AD cortical tissue, [(3)H]AZD2184 and antibodies to human beta-amyloid labeled identical structures. In vivo administration of [(3)H]AZD2184 to APP/PS1 mice further showed that [(3)H]AZD2184 labels amyloid deposits with low non-specific background binding. Taken together, the pre-clinical profile of AZD2184 in relation to the reference ligand PIB, suggests that (11)C-labeled AZD2184 is a potential radioligand for PET-visualization of beta-amyloid deposits in the living human brain.
Journal of Neurochemistry 01/2009; 108(5):1177-86. · 4.06 Impact Factor
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ABSTRACT: The serotonin transporter radioligand [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, or [11C]DASB, was examined in order to assess its potential for measuring fluctuations in endogenous serotonin concentrations with positron emission tomography. Binding characteristics of [11C]DASB and the propensity for serotonin to displace the tracer were explored in rat brain homogenates. Experiments showed that serotonin displaced [11C]DASB in vitro. Ex vivo experiments performed after tranylcypromine injection (3 or 15 mg/kg) showed a dose-dependent trend in radioactivity uptake and suggested that serotonin may compete with [11C]DASB for transporter binding.
Nuclear Medicine and Biology 03/2005; 32(2):129-36. · 3.02 Impact Factor
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ABSTRACT: WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-desmethyl derivative DWAY 2 are well-known high affinity 5-HT(1A) receptor antagonists, which when labeled with carbon-11 (beta+; t(1/2) = 20.4 min) in the carbonyl group are effective radioligands for imaging brain 5-HT(1A) receptors with positron emission tomography (PET). In a search for new 5-HT(1A) antagonists with different pharmacokinetic and metabolic properties, the pyridinyl N-oxide moiety was incorporated into analogs of 1 and 2. NOWAY 3, in which the pyridinyl ring of 1 was oxidized to the pyridinyl N-oxide, was prepared via nucleophilic substitution of 2-[4-(2-methoxyphenyl)piperazin-1-yl]ethylamine on 2-chloropyridine-N-oxide followed by acylation with cyclohexanecarbonyl chloride. 6Cl-NOWAY 4, a more lipophilic (pyridinyl-6)-chloro derivative of 3, was prepared by treating 1-(2-methoxyphenyl)-4-(2-(2-(6-bromo)aminopyridinyl-N-oxide)ethyl)piperazine with cyclohexanecarbonyl chloride for acylation and concomitant chloro for bromo substitution. NEWWAY 5, in which the 2-hydroxy-phenyl group of 2 is replaced with a 2-pyridinyl N-oxide group with the intention of mimicking the topology of 2, was prepared in five steps from 2-(chloroacetylamino)pyridine. N-Oxides 3-5 were found to be high affinity antagonists at 5-HT(1A) receptors, with 3 having the highest affinity and a Ki value (0.22 nM) comparable to that of 1 (0.17 nM). By calculation the lipophilicity of 3 (LogP = 1.87) is lower than that of 1 by 1.25 LogP units while TLC and reverse phase HPLC indicate that 3 has slightly lower lipophilicity than 1. On the basis of these encouraging findings, the N-oxide 3 was selected for labeling with carbon-11 in its carbonyl group and for evaluation as a radioligand with PET. After intravenous injection of [carbonyl-11C]3 into cynomolgus monkey there was very low uptake of radioactivity into brain and no PET image of brain 5-HT(1A) receptors was obtained. Either 3 inadequately penetrates the blood-brain barrier or it is excluded from brain by an active efflux mechanism. Rapid deacylation of 3 was not apparent in vivo; in cynomolgus monkey plasma radioactive metabolites of [carbonyl-11C]3 appeared less rapidly than from the radioligands [carbonyl-11C]1 and [carbonyl-11C]2, which are known to be primarily metabolized by deacylation. Ligand 3 may have value as a new pharmacological tool, but not as a radioligand for brain imaging.
Bioorganic & Medicinal Chemistry 03/2005; 13(3):883-93. · 2.92 Impact Factor
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William E Klunk,
Henry Engler,
Agneta Nordberg,
Yanming Wang,
Gunnar Blomqvist,
Daniel P Holt,
Mats Bergström,
Irina Savitcheva,
Guo-feng Huang,
Sergio Estrada, [......],
Manik L Debnath,
Julien Barletta,
Julie C Price, Johan Sandell,
Brian J Lopresti,
Anders Wall,
Pernilla Koivisto,
Gunnar Antoni,
Chester A Mathis,
Bengt Långström
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ABSTRACT: This report describes the first human study of a novel amyloid-imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94-fold, p = 0.0001). Large increases also were observed in parietal (1.71-fold, p = 0.0002), temporal (1.52-fold, p = 0.002), and occipital (1.54-fold, p = 0.002) cortex and the striatum (1.76-fold, p = 0.0001). PIB retention was equivalent in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 years) and six older healthy controls (69.5 +/- 11 years) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metabolism determined with 18F-fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = -0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.
Annals of Neurology 04/2004; 55(3):306-19. · 11.09 Impact Factor
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ABSTRACT: 5-Methyl-6-nitroquipazine, a novel analogue of the potent and selective serotonin transporter inhibitor 6-nitroquipazine was synthesized and radiolabeled with tritium and the positron emitter carbon-11. [3H]5-methyl-6-nitroquipazine was found to have a K(d)=51+/-7 pM. The high affinity and the facile labeling of [11C]5-methyl-6-nitroquipazine makes it a promising radioligand for visualization of the serotonin transporter with positron emission tomography.
Bioorganic & Medicinal Chemistry Letters 01/2003; 12(24):3611-3. · 2.55 Impact Factor
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ABSTRACT: Vinpocetine is a compound widely used in the prevention and treatment of cerebrovascular diseases. The exact mechanism of action of the drug is still not known. The objective of the present investigation was to determine the global uptake and regional distribution of radiolabelled vinpocetine in the human brain. Three healthy persons were examined with positron emission tomography (PET) and [11C]-vinpocetine.
The uptake of [11C]-vinpocetine in brain was rapid and on average as a maximum 3.7% of the total radioactivity injected was in the brain 2 minutes after radioligand administration. The uptake was heterogeneously distributed among brain regions. When compared with the cerebellum, an a priori reference region, the highest regional uptake was in the thalamus, the upper brain stem, the striatum and the cortex.
The brain regions showing increased uptake in the human brain correspond to those in which vinpocetine has previously been shown to induce elevated metabolism and blood flow by PET clinical studies in patients with chronic ischaemic post-stroke condition.
Orvosi Hetilap 12/2002; 143(47):2631-6.
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ABSTRACT: The false adrenergic neurotransmitter [11C]meta-hydroxyephedrine ([11C]HED) is currently the PET tracer of choice for assessment of myocardial sympathetic innervation. The molecule is metabolised in the 4-position of the aromatic ring. The resulting radiolabelled metabolites need to be measured in order to obtain an arterial input function. Our aim was the development of a PET tracer with an increased metabolic stability relative to [11C]HED. We selected 4-methylmetaraminol as a candidate molecule for radiolabelling with 11C (t1/2 20.4 min). Our radiosynthetic approach towards 4-[11C]methylmetaraminol involved a palladium-catalyzed cross-coupling reaction of a protected 4-trimethylstannyl derivative of metaraminol with [11C]methyl iodide followed by removal of the protective groups. 4-[11C]methylmetaraminol was obtained in a final decay-corrected radiochemical yield of 20–25% within a synthesis time of 60–80 min. The specific radioactivity at the end of the synthesis ranged from 18–37 to GBq/μmol. The unlabelled reference molecule, 4-methylmetaraminol, was prepared in a 5-step synthesis starting from metaraminol. A biological evaluation of 4-[11C]methylmetaraminol is in progress and the results will be reported elsewhere. Copyright © 2002 John Wiley & Sons, Ltd.
Journal of Labelled Compounds 11/2002; 46(1):55 - 65.
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ABSTRACT: PET provides the potential to quantify the distribution of radiolabelled drugs in the human body. In cases when radiolabelled compounds undergo metabolic transformation after administration in vivo, it is necessary to examine the kinetics and distribution of both the labeled mother compound and labeled metabolites. The objective of this study was to assess the extent by which 11C-labeled ethanol, the product arising from the de-esterification of the neuroprotective drug vinpocetine (ethyl-apovincaminate), might contribute to the regional cerebral radioactivity measured by PET after the administration of [ethyl-11C]vinpocetine. In three cynomolgous monkeys PET measurements were made after intravenous bolus injection of both [11C]vinpocetine and 1-[11C]ethanol. There was a marked difference between the regional time-activity curves of [11C]ethanol and [11C]vinpocetine. The distribution pattern obtained with [11C]ethanol was similar to that observed with blood flow tracers such as [15O]water and [15O]butanol. The study shows that although [11C]ethanol may moderately contribute to the brain radioactivity distribution pattern of [11C]vinpocetine, the rapid degradation of [11C]ethanol makes it unlikely that the contribution of this metabolite is of importance. The distinct distribution patterns and kinetics of [11C]vinpocetine and [11C]ethanol also support the view, obtained from our previous observations, that vinpocetine may bind to specific sites in the monkey and human brain, especially in the thalamus.
Nuclear Medicine and Biology 11/2002; 29(7):753-9. · 3.02 Impact Factor
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ABSTRACT: Direct information on the distribution of a drug requires measurements in various tissues. Such data have until now been obtained in animals, or have indirectly been calculated from plasma measurements in humans using mathematical models. Here we suggest the use of positron emission tomography (PET) as a method to obtain direct measurements of drug distribution in the human body. The distribution in body and brain of vinpocetine, a neuroprotective drug widely used in the prevention and treatment of cerebrovascular diseases, was followed after oral administration. Vinpocetine was labelled with carbon-11 and radioactivity was measured by PET in stomach, liver, brain and kidney in six healthy volunteers. The radioactivity in blood and urine as well as the fractions of [(11)C]vinpocetine and labelled metabolites in plasma were also determined. After oral administration, [(11)C]vinpocetine appeared immediately in the stomach and within minutes in the liver and the blood. In the blood the level of radioactivity continuously increased until the end of the measurement period, whereas the fraction of the unchanged mother compound decreased. Radioactivity uptake and distribution in the brain were demonstrable from the tenth minute after the administration of the labelled drug. Brain distribution was heterogeneous, similar to the distribution previously reported after intravenous administration. These findings indicate that vinpocetine, administered orally in humans, readily enters the bloodstream from the stomach and gastrointestinal tract and, consequently, passes the blood-brain barrier and enters the brain. Radioactivity from [(11)C]vinpocetine was also demonstrated in the kidneys and in urine, indicating that at least a part of the radioactive drug and labelled metabolites is eliminated from the body through the kidneys. This study is the first to demonstrate that PET might be a useful, direct and non-invasive tool to study the distribution and pharmacokinetics of orally administered labelled CNS drugs in the living human body.
European journal of nuclear medicine and molecular imaging 09/2002; 29(8):1031-8. · 4.99 Impact Factor
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ABSTRACT: Radiohalogenated 5-halo-6-nitroquipazine analogues have been shown to be potential radioligands for visualization of the serotonin transporter (5-HTT) with PET and SPECT. In the present study a methylated analogue, 5-methyl-6-nitroquipazine (MNQP), was radiolabeled with carbon-11 in a two step reaction via a palladium catalyzed cross coupling reaction between N-t-BOC-protected 5-tributylstannyl-6-nitroquipazine and [(11)C]methyl iodide as key step. [(11)C]MNQP was examined in the cynomolgus monkey brain with positron emission tomography (PET) and the appearance of labeled metabolites in monkey plasma was measured with gradient HPLC. Radioactivity increased continuously in all brain regions during the 90 minutes acquisition time. Highest accumulation of radioactivity was observed in the thalamus and brainstem, regions with a known high density of 5-HTT. The calculated ratios between the thalamus and brainstem to the 5-HTT poor cerebellum were 1.5 and 1.3-1.4, respectively, 80 minutes after radioligand injection. Pretreatment with citalopram prior to the PET measurement markedly reduced the binding in the thalamus and the brainstem. At 15 and 30 minutes after injection of [(11)C]MNQP approximately 90% and 60%, respectively, of radioactivity in plasma represented unchanged radioligand. The slow kinetics and moderate ratios recorded however, may limit its use as a PET radioligand for quantitative studies of the serotonin transporter with PET.
Nuclear Medicine and Biology 09/2002; 29(6):651-6. · 3.02 Impact Factor
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ABSTRACT: NAD-299 is a selective 5-HT(1A) receptor antagonist that is currently developed as a putative antidepressant drug. [(11)C]NAD-299 was examined in the cynomolgus monkey brain with positron emission tomography (PET). After radioligand injection high accumulation of radioactivity was observed in the frontal and temporal cortex and the raphe nuclei, regions known to contain a high density of 5-HT(1A) receptors. Peak equilibrium appeared already at about 10 min after i.v. injection. Pre-treatment with a high dose of the antagonist WAY-100635 reduced the amount of radioactivity in the cortex and the raphe to the level of the cerebellum. A strong pre-treatment effect could also be achieved using pindolol, a partial agonist at the 5-HT(1A)-receptors. The appearance of labeled metabolites in monkey plasma was measured with HPLC. At 45 minutes after injection 49% (range 27-55%, n = 5) of radioactivity in monkey plasma represented unchanged radioligand. [(11)C]NAD-299 was metabolized to more polar labeled metabolites of which one has the same chromatographic mobility as the descyclobutyl analogue of NAD-299 (NAD-272). The results indicate that [(11)C]NAD-299 has potential as a PET radioligand for studies of 5-HT(1A) receptors in the primate brain.
Nuclear Medicine and Biology 02/2002; 29(1):39-45. · 3.02 Impact Factor
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ABSTRACT: Imaging by scintigraphy the serotonin transporter (5-HTT) in the living human brain would be of great value in research on the pathophysiology and treatment of neuropsychiatric disorders such as depression. For that reason, and in order to obtain a selective radiotracer applicable to PET, we report here the carbon-11 labelling of a selective 5-HTT radioligand: N, N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine or MADAM in two different positions: [p-11C-methyl]MADAM and [N-11C-methyl]MADAM. The synthesis of Bu3Sn-ADAM and N-dimethyl-MADAM is described. [p-11C-methyl]MADAM was obtained by a Stille coupling reaction between Bu3Sn-ADAM and [11C]methyl iodide using palladium (0) as a catalyst without (Ia) or with copper chloride as a co-catalyst (Ib). [N-11C-methyl]MADAM was obtained by an N-methylation reaction between N-demethyl-MADAM and [11C]methyl iodide (II). The carbon-11 incorporation yield in [p-11C-methyl]MADAM was 10–30% (Ia and Ib) and in [N-11C-methyl]MADAM was 75-80% (II). The final product in each case was obtained in 30 min total synthesis time, including HPLC purification and with >99% radiochemical purity. Copyright © 2001 John Wiley & Sons, Ltd.
Journal of Labelled Compounds 11/2001; 44(14):1013 - 1023.
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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.
Journal of Labelled Compounds 02/2001; 44(2):113 - 120.
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ABSTRACT: Research on depression and anxiety disorders would benefit from the development of suitable radioligands for PET-imaging of the serotonin transporter. Three cocaine analogues, 2β-carbomethoxy-3β-(3′-iodo-4′-methyl, -ethyl and isopropyl phenyl)nortropane (LBT-14, EINT and LBT-44), were prepared in a three-step synthesis by 1-4 addition of the appropriate Grignard reagent to anhydroecgonine methyl ester as first step. Iodination of the phenyl ring was accomplished with a mixture of yellow mercuric oxide, perchloric acid and acetic acid followed by a solution of iodine in dichloromethane. N-desmethylation was performed by using 2,2,2-trichloroethylchloroformiate followed by treatment of zinc in acetic acid. Acidic hydrolysis of the ester functions gave the carboxylic acid analogues of LBT-14, EINT and LBT-44. The precursors were labelled with 11C using [11C]methyl iodide or [11C] methyl triflate in dimethyl formamide (DMF) and tetrabutyl ammonium hydroxide (TBAH) as base. [11C]LBT-14, [11C]EINT and [11C]LBT-44 were all examined in Cynomolgus monkey with PET. All three compounds entered the monkey brain to a high degree (5∽–10% of injected dose). There was a marked uptake of radioactivity in the thalamus and the brain stem, regions known to contain serotinin transporters. Pre-treatment with the selective serotonin transporter inhibitor citalopram had minor effect on the binding ratios, suggesting that none of the three examined radioligands are preferable to the previously examined non-iodinated 4′-isopropenyl analogue [11C]RTI-357 for the study of the serotonin reuptake system with PET. Copyright © 2000 John Wiley & Sons, Ltd.
Journal of Labelled Compounds 09/2000; 43(10):1033 - 1046.
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ABSTRACT: [11C]FLB 457 is a high affinity dopamine D2 receptor radioligand that is used for visualisation and quantitation of extrastriatal dopamine D2 receptors with positron emission tomography (PET). In this study, we report a comparison regarding the specific radioactivity of [11C]FLB 457 obtained by two different methods of synthesising [11C]methyl iodide. In addition, the synthesis of unlabelled FLB 457 and the corresponding desmethyl-precursor, starting from commercially available material, is reported. The first method used for [11C]methyl iodide synthesis was reduction of [11C]CO2 with lithium aluminium hydride in tetrahydrofuran to [11C]CH3OH, followed by conversion into [11C]CH3I= with hydrogen iodide. The second, recently developed method uses gas phase halogenation of [11C]CH4 with iodine. [11C]FLB 457 was labelled with [11C]methyl triflate produced on-line from [11C]methyl iodide. With the first method a specific radioactivity for [11C]FLB 457 of 2100 Ci/mmol (78 GBq/μmol) (n=13) at 40 min after end of bombardment (EOB) was achieved. Using the gas phase method a specific radioactivity of 3400 Ci/mmol (126 GBq/μmol) (n=7) at 40 min EOB could be obtained. The use of the gas phase method also resulted in shorter time for set-up compared to the regular method since no wet chemistry is involved in the preparation of [11C]methyl iodide. Copyright © 2000 John Wiley & Sons, Ltd.
Journal of Labelled Compounds 04/2000; 43(4):331 - 338.
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ABSTRACT: Desmethyl-raclopride was synthesized via a straightforward, three-step synthetic approach and used for the preparation of [11C]raclopride from [11C]methyl triflate. Conditions for the radiolabelling were optimized to obtain a simple and reproducible procedure suitable for automation. [11C]Raclopride was prepared with an average radiochemical yield of 55–65% (decay corrected, based on starting [11C]methyl triflate) in a total synthesis time (including purification and formulation of product) of 35 min. The radiolabelling procedure used significantly less precursor, avoided the use of DMSO, and was shorter compared to the standard radiolabelling procedure with [11C]methyl iodide. Copyright © 1999 John Wiley & Sons, Ltd.
Journal of Labelled Compounds 12/1999; 42(12):1183 - 1193.
