Keith G. Poole

MRC Clinical Sciences Centre, London Borough of Harrow, England, United Kingdom

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Publications (17)23.46 Total impact

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    ABSTRACT: Fluticasone propionate (FP) is a potent anti-inflammatory synthetic steroid, used for the treatment of asthma. Flixotide™ is a formulated pressurized metered-dose inhaler (pMDI) that contains small-micronized FP particles in a blend of CFC propellants. Our objective was to develop a radiotracer method for accurately measuring the regional deposition of FP within the human lung using positron emission tomography (PET), which would be of important clinical interest. Flixotide™ pMDIs were used to prepare [18F]FP pMDIs labeled isotopically with the positron emitter, fluorine-18 (t1/2=109.7 min). FP particles from Flixotide™ pMDIs were mixed with [18F]FP formulated into a pMDI and sonicated at room temperature. The drug delivery of [18F]FP pMDI (250 μg of FP per actuation dose) was assessed for particle size distribution and dose uniformity. The distributions of FP and [18F]FP across particle size in such preparations were measured with an Andersen cascade impactor. This procedure was shown to provide an emitted dose from a [18F]FP pMDI of 246±19 μg/per metered dose. The particle size distribution as measured by mass median aerodynamic diameter (MMAD) (The mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD) for each distribution were calculated. MMAD is defined as the aerodynamic diameter around which the mass of particles is equally distributed and the GSD is a measure of the dispersion of these particle diameters around the MMAD) from a commercial Flixotide™ pMDI was 2.6±0.2 μm and agreed well with that from an [18F]FP pMDI (2.8±0.1 μm). The MMAD and geometric standard deviation (GSD) of newly formulated [18F]FP pMDIs were unaffected by the formulation procedure. [18F]FP was distributed with good uniformity with respect to the mass of FP for particles greater than 0.43 μm. Hence, the radiolabeled pMDI is a suitable source of radiotracer for the regional measurement of lung deposition for inhaled FP in human subjects with PET. Copyright © 2003 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 12/2003; 47(1):55 - 70.
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    ABSTRACT: Radiolabelled compounds formulated for injection (radiopharmaceuticals), are increasingly being employed in drug development studies. These can be used in tracer amounts for either pharmacokinetic or pharmacodynamic studies. Such radiotracer studies can also be carried out early in man, even prior to conventional Phase I clinical testing. The aim of this document is to describe procedures for production and safety testing of oncology radiotracers developed for imaging by positron emission tomography in cancer patients. We propose strategies for overcoming the inability to produce compounds in sufficient quantities via the radiosynthetic routes for full chemical characterisation and toxicology testing including (i) independent confirmation as far as possible that the stable compound associated with the radiopharmaceutical is identical to the non-labelled compound, (ii) animal toxicity studies with > or = 10 times (typically 100 times) the intended tracer dose in humans scaled by body surface area, and (iii) patient monitoring during the radiotracer positron emission tomography clinical trial.
    British Journal of Cancer 04/2002; 86(7):1052-6. · 5.08 Impact Factor
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    ABSTRACT: The adenosine A2A antagonist, KF18446 was labelled in the aromatic O-methyl position using [11C]iodomethane. [4-O-methyl-11C]KF18446 and [4-O-methyl-11C]KW-6002, an adenosine A2A antagonist that we radiolabelled previously, were evaluated in rats. In brain, both [4-O-methyl-11C]KW-6002 and [4-O-methyl-11C]KF18446 showed the highest uptake in striata and lowest in frontal cortex. For [4-O-methyl-11C]KW-6002 maximal striata: frontal cortex ratio was 1.7 from 60 to 120 min. For [4-O-methyl-11C]KF18446 maximal striata: frontal cortex ratio was 2.4 from 30 to 90 min. The amount of unchanged [4-O-methyl-11C]KW-6002 was > 98 % in striata and cerebellum at 75 min post-injection.
    Journal of Labelled Compounds 05/2001; 44(S1).
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    ABSTRACT: A14-Iodoinsulin is a close biochemical and pharmacological mimic of insulin. Human insulin was labelled in its A chain tyrosine-14 residue by direct iodination with the positron-emitter iodine-124 (β+=25.6%; t1/2=4.15 days) to provide a radiotracer for imaging with positron emission tomography (PET). Several reagents were compared for conversion of cyclotron-produced [124I]iodide into a reactive species for the labelling reaction. Radiochemical yields from the use of Iodo-Gen®, Chloramine-T, N-bromosuccinimide or lactoperoxidase–hydrogen peroxide were similar [35% (n=1), 33±9% (n=10), 32±11% (n=25) or 33% (n=2), respectively]. [124I]A14-Iodoinsulin was separated from unreacted insulin and radioactive by-products by tandem reverse phase HPLC and rapidly formulated for intravenous injection by adsorption on a Sep-Pak tC18-Plus® cartridge, followed by elution with 10 mM hydrochloric acid–ethanol (1:1 v/v, 1 ml). This radiotracer can now be obtained in useful radioactivities at high effective specific radioactivity and is now being applied to PET studies of its biodistribution in living subjects. Copyright © 2001 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 04/2001; 44(6):465 - 480.
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    ABSTRACT: The adenosine A2A antagonist, KF18446 was labelled in the aromatic O‐methyl position using [11C]iodomethane. [4‐O‐methyl‐11C]KF18446 and [4‐O‐methyl‐11C]KW‐6002, an adenosine A2A antagonist that we radiolabelled previously, were evaluated in rats. In brain, both [4‐O‐methyl‐11C]KW‐6002 and [4‐O‐methyl‐11C]KF18446 showed the highest uptake in striata and lowest in frontal cortex. For [4‐O‐methyl‐11C]KW‐6002 maximal striata: frontal cortex ratio was 1.7 from 60 to 120 min. For [4‐O‐methyl‐11C]KF18446 maximal striata: frontal cortex ratio was 2.4 from 30 to 90 min. The amount of unchanged [4‐O‐methyl‐11C]KW‐6002 was > 98 % in striata and cerebellum at 75 min post‐injection.
    Journal of Labelled Compounds and Radiopharmaceuticals 01/2001; 44. · 1.24 Impact Factor
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    ABSTRACT: 2-[11C]Thymidine has been produced from [11C]methane via [11C]phosgene and [11C]urea. Anhydrous [11C]urea was prepared from [11C]phosgene by reaction with liquid ammonia. This novel approach avoids the problems associated with the synthesis of anhydrous [11C]urea from [11C]cyanide. A fully automated system based on a modular approach and under PLC control has been developed. The system provides 2-[11C]thymidine reliably and reproducibly for clinical PET studies. The radiosynthesis takes 45-50 min from [11C]methane and the average yield was 1.5-3.3 GBq (40-90 mCi). The specific radioactivity was typically in the range 29.6-51.8 GBq mumol-1 (0.8-1.4 Ci mumol-1) at EOS corresponding to 6-12 micrograms of stable thymidine. The radiochemical yield of 2-[11C]thymidine was ca. 14% from [11C]methane.
    Applied Radiation and Isotopes 11/1999; 51(4):377-88. · 1.18 Impact Factor
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    ABSTRACT: The production and quality control analysis of short-lived (t1/2=2.03 min) oxygen-15 labelled gases ([]O2, []CO, and []CO2) from a Cyclone 3D accelerator for positron emission tomography (PET) in human subjects has been established and evaluated on a routine basis use at the MRC Cyclotron Unit and are here described. Contaminant levels have been identified and measured by radio-gas chromatography. The maximum levels allowed, measured as a percentage of total delivered activity (v/v), are 3.7% for total nitrogen oxides and 1% for []CO in []CO2 and []CO2 in []CO. By adjunction of a cryogenic or molecular sieve trap, radiopharmaceutical gases are routinely produced well within these specifications.
    Applied Radiation and Isotopes 01/1999; 51(4):403-409. · 1.18 Impact Factor
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    ABSTRACT: 2-[]Thymidine has been produced from []methane via []phosgene and []urea. Anhydrous []urea was prepared from []phosgene by reaction with liquid ammonia. This novel approach avoids the problems associated with the synthesis of anhydrous []urea from []cyanide. A fully automated system based on a modular approach and under PLC control has been developed. The system provides 2-[]thymidine reliably and reproducibly for clinical PET studies. The radiosynthesis takes 45–50 min from []methane and the average yield was 1.5–3.3 GBq (40–90 mCi). The specific radioactivity was typically in the range 29.6–51.8 GBq μmol−1 (0.8–1.4 Ci μmol−1) at EOS corresponding to 6–12 μg of stable thymidine. The radiochemical yield of 2-[]thymidine was ca. 14% from []methane.
    Applied Radiation and Isotopes. 01/1999;
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    ABSTRACT: WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl))-N-(2-pyridyl)-cyclohexanecarboxamide], when labelled in its carbonyl position with carbon-11 (t1/2 = 20.4 min), is an effective radioligand for the study of 5-HT1A receptors in human brain with positron emission tomography (PET). A simple remotely-controlled procedure was developed for the routine synthesis of [carbonyl-11C]WAY-100635. Thus, cyclohexylmagnesium chloride is coated onto the inner surface of a narrow polypropylene tube. Cyclotron-produced [11C]carbon dioxide is passed into the tube in a nitrogen stream. A solution of thionyl chloride in tetrahydrofuran is then passed through the tube to convert the trapped radioactive adduct into [carbonyl-11C]cyclohexanecarbonyl chloride and to release this labelling agent into a vial containing 1-(2-methoxyphenyl)-4-(2-(2-pyridylamino)ethyl)piperazine plus triethylamine. The vial is sealed and heated to 70°C for 5 min. [carbonyl-11C]WAY-100635 is isolated by sample-enrichment and reverse phase HPLC and formulated for human intravenous injection by evaporation of solvent and dissolution in ‘saline for injection’. The novel use of the immobilized Grignard reagent has the advantages that only small quantities of all reagents are required so simplifying product purification. Moreover, the procedure was readily adapted for operation in a shielded hot-cell with remote control for radiation safety. The remotely-controlled radiosynthesis takes 45 min and gives high radioactivities (2.96–5.92 GBq) of formulated [carbonyl-11C]WAY-100635 in > 99% radiochemical purity and high specific radioactivity (average, 192 GBq/μmol).
    Journal of Labelled Compounds 12/1998; 38(10):941 - 953.
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    ABSTRACT: [carbonyl-11C]Desmethyl-WAY-100635 (DWAY) is possibly a low-level metabolite appearing in plasma after intravenous administration of [carbonyl-11C]WAY-100635 to human subjects for positron emission tomographic (PET) imaging of brain 5-HT1A receptors. In this study we set out to assess the ability of DWAY to enter brain in vivo and to elucidate its possible interaction with 5-HT1A receptors. Desmethyl-WAY-100635 was labelled efficiently with carbon-11 (t1/2 = 20.4 min) in high specific radioactivity by reaction of its descyclohexanecarbonyl analogue with [carbonyl-11C]cyclohexanecarbonyl chloride. The product was separated in high radiochemical purity by high-performance liquid chromatography (HPLC) and formulated for intravenous injection. Rats were injected intravenously with DWAY, sacrificed at known times and dissected to establish radioactivity content in brain tissues. At 60 min after injection, the ratios of radioactivity concentration in each brain region to that in cerebellum correlated with previous in vitro and in vivo measures of 5-HT1A receptor density. The highest ratio was about 22 in hippocampus. Radioactivity cleared rapidly from plasma; HPLC analysis revealed that DWAY represented 55% of the radioactivity in plasma at 5 min and 33% at 30 min. Only polar radioactive metabolites were detected. Subsequently, a cynomolgus monkey was injected intravenously with DWAY and examined by PET. Maximal whole brain uptake of radioactivity was 5.7% of the administered dose at 5 min after injection. The image acquired between 9 and 90 min showed high radioactivity uptake in brain regions rich in 5-HT1A receptors (e.g. frontal cortex and neocortex), moderate uptake in raphe nuclei and low uptake in cerebellum. A transient equilibrium was achieved in cortical regions at about 60 min, when the ratio of radioactivity concentration in frontal cortex to that in cerebellum reached 6. The corresponding ratio for raphe nuclei was about 3. Radioactive metabolites appeared rapidly in plasma, but these were all more polar than DWAY, which represented 52% of the radioactivity in plasma at 4 min and 20% at 55 min. In a second PET experiment, in which a cynomolgus monkey was pretreated with the selective 5-HT1A receptor antagonist, WAY-100635, at 25 min before DWAY injection, radioactivity in all brain regions was reduced to that in cerebellum. Autoradiography of post mortem human brain cryosections after incubation with DWAY successfully delineated 5-HT1A receptor distribution. Receptor-specific binding was eliminated in the presence of the selective 5-HT1A receptor agonist, 8-OH-DPAT [(+/-)-8-hydroxy-2-dipropylaminotetralin]. These findings show that: (a) intravenously administered DWAY is well able to penetrate brain in rat and monkey, (b) DWAY is a highly effective radioligand for brain 5-HT1A receptors in rat and monkey in vivo and for human brain in vitro, and (c) the metabolism and kinetics of DWAY appear favourable to successful biomathematical modelling of acquired PET data. Thus, DWAY warrants further evaluation as a radioligand for PET studies of 5-HT1A receptors in human brain.
    European Journal of Nuclear Medicine 04/1998; 25(4):338-46.
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    ABSTRACT:  [carbonyl-11C]Desmethyl-WAY-100635 (DWAY) is possibly a low-level metabolite appearing in plasma after intravenous administration of [carbonyl-11C]WAY-100635 to human subjects for positron emission tomographic (PET) imaging of brain 5-HT1A receptors. In this study we set out to assess the ability of DWAY to enter brain in vivo and to elucidate its possible interaction with 5-HT1A receptors. Desmethyl-WAY-100635 was labelled efficiently with carbon-11 (t 1/2=20.4min) in high specific radioactivity by reaction of its descyclohexanecarbonyl analogue with [carbonyl-11C]cyclohexanecarbonyl chloride. The product was separated in high radiochemical purity by high-performance liquid chromatography (HPLC) and formulated for intravenous injection. Rats were injected intravenously with DWAY, sacrificed at known times and dissected to establish radioactivity content in brain tissues. At 60min after injection, the ratios of radioactivity concentration in each brain region to that in cerebellum correlated with previous in vitro and in vivo measures of 5-HT1A receptor density. The highest ratio was about 22 in hippocampus. Radioactivity cleared rapidly from plasma; HPLC analysis revealed that DWAY represented 55% of the radioactivity in plasma at 5min and 33% at 30min. Only polar radioactive metabolites were detected. Subsequently, a cynomolgus monkey was injected intravenously with DWAY and examined by PET. Maximal whole brain uptake of radioactivity was 5.7% of the administered dose at 5min after injection. The image acquired between 9 and 90min showed high radioactivity uptake in brain regions rich in 5-HT1A receptors (e.g. frontal cortex and neocortex), moderate uptake in raphe nuclei and low uptake in cerebellum. A transient equilibrium was achieved in cortical regions at about 60min, when the ratio of radioactivity concentration in frontal cortex to that in cerebellum reached 6. The corresponding ratio for raphe nuclei was about 3. Radioactive metabolites appeared rapidly in plasma, but these were all more polar than DWAY, which represented 52% of the radioactivity in plasma at 4min and 20% at 55min. In a second PET experiment, in which a cynomolgus monkey was pretreated with the selective 5-HT1A receptor antagonist, WAY-100635, at 25min before DWAY injection, radioactivity in all brain regions was reduced to that in cerebellum. Autoradiography of post mortem human brain cryosections after incubation with DWAY successfully delineated 5-HT1A receptor distribution. Receptor-specific binding was eliminated in the presence of the selective 5-HT1A receptor agonist, 8-OH-DPAT [(±)-8-hydroxy-2-dipropylaminotetralin]. These findings show that: (a) intravenously administered DWAY is well able to penetrate brain in rat and monkey, (b) DWAY is a highly effective radioligand for brain 5-HT1A receptors in rat and monkey in vivo and for human brain in vitro, and (c) the metabolism and kinetics of DWAY appear favourable to successful biomathematical modelling of acquired PET data. Thus, DWAY warrants further evaluation as a radioligand for PET studies of 5-HT1A receptors in human brain.
    European journal of nuclear medicine and molecular imaging 03/1998; 25(4):338-346. · 5.11 Impact Factor
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    ABSTRACT: Propionyl-L-carnitine (PLC) is under development as a therapeutic for the treatment of peripheral artery disease, coronary heart disease and chronic heart failure. Three methods were examined for labelling PLC in its propionyl group with positron-emitting carbon-11 (t12 = 20.3 min), one chemical and two chemoenzymatic. The former was based on the preparation of [11C]propionyl chloride as labelling agent via 11C-carboxylation of ethylmagnesium bromide with cyclotron-produced [11C]carbon dioxide and subsequent chlorination. Reaction of carrier-added [11C]propionyl chloride with L-carnitine in trifluoroacetic acid gave [11C]PLC in 12% radiochemical yield (decay-corrected) from cyclotron-produced [11C]carbon dioxide. However, the radiosynthesis was unsuccessful at the no-carrier-added (NCA) level of specific radioactivity. [11C]Propionate, as a radioactive precursor for chemoenzymatic routes, was prepared via carboxylation of ethylmagnesium bromide with [11C]carbon dioxide and hydrolysis. NCA [11C]PLC was prepared in 68 min in 14% radiochemical yield (decay-corrected) from [11C]propionate via sequential conversions catalysed by acetate kinase, phosphotransacetylase and carnitine acetyltransferase. A superior chemoenzymatic synthesis of NCA [11C]PLC was developed, based on the use of a novel supported Grignard reagent for the synthesis of [11C]propionate and conversions by S-acetyl-CoA synthetase and carnitine acetyltransferase. This gave an overall radiochemical yield of 30-48% (decay-corrected). This synthesis was automated for radiation safety and provides pure NCA [11C]PLC in high radioactivities ready for intravenous administration within 25 min from radionuclide production. The [11C]PLC is suitable for pharmacokinetic studies in human subjects with PET and the elucidation of the fate of the propionyl group of PLC in vivo.
    Applied Radiation and Isotopes 08/1997; 48(7):917-24. · 1.18 Impact Factor
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    ABSTRACT: WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl))-N-(2-pyridyl)-cyclohexanecarboxamide], when labelled in its carbonyl position with carbon-11 (t1/2 = 20.4 min), is an effective radioligand for the study of 5-HT1A receptors in human brain with positron emission tomography (PET). A simple remotely-controlled procedure was developed for the routine synthesis of [carbonyl-11C]WAY-100635. Thus, cyclohexylmagnesium chloride is coated onto the inner surface of a narrow polypropylene tube. Cyclotron-produced [11C]carbon dioxide is passed into the tube in a nitrogen stream. A solution of thionyl chloride in tetrahydrofuran is then passed through the tube to convert the trapped radioactive adduct into [carbonyl-11C]cyclohexanecarbonyl chloride and to release this labelling agent into a vial containing 1-(2-methoxyphenyl)-4-(2-(2-pyridylamino)ethyl)piperazine plus triethylamine. The vial is sealed and heated to 70°C for 5 min. [carbonyl-11C]WAY-100635 is isolated by sample-enrichment and reverse phase HPLC and formulated for human intravenous injection by evaporation of solvent and dissolution in ‘saline for injection’. The novel use of the immobilized Grignard reagent has the advantages that only small quantities of all reagents are required so simplifying product purification. Moreover, the procedure was readily adapted for operation in a shielded hot-cell with remote control for radiation safety. The remotely-controlled radiosynthesis takes 45 min and gives high radioactivities (2.96–5.92 GBq) of formulated [carbonyl-11C]WAY-100635 in > 99% radiochemical purity and high specific radioactivity (average, 192 GBq/μmol).
    Journal of Labelled Compounds 01/1996; 38(10):941-953.
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    ABSTRACT: The selective 5-HT1A receptor radioligand, [11C]WAY-100635 {[11C]N-2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridyl)cyclohexanecarboxamide}, has been injected intravenously into healthy male volunteers and studied by PET (positron emission tomography). The results provide the first delineation of 5-HT1A receptors in living human brain and demonstrate the potential to use [11C]WAY-100635 for the study of central 5-HT1A receptors in patients with psychiatric and neurological disorders and for the investigation of the pharmacology of drugs acting on the central nervous system.
    European Journal of Pharmacology 10/1995; · 2.59 Impact Factor
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    ABSTRACT: The prospective therapeutic, propionyl-L-carnitine, was labelled in the N-methyl position with the positron-emitter, carbon-11 (t1/2 = 20.4 min), with a view to studying its pharmacokinetics in humans using PET. Labelling was achieved by methylating nor-propionyl-L-carnitine hydrochloride with no-carrier-added [11C]iodomethane (produced from cyclotron-produced [11C]carbon dioxide) in ethanol in the presence of 1,2,2,6,6-pentamethylpiperidine. HPLC of the reaction mixture on a strong cation exchange column provided high purity [N-methyl-11C]propionyl-L-carnitine in 62% radiochemical yield (decay-corrected from [11C]iodomethane), ready for intravenous administration within 35 min from the end of radionuclide production. [N-methyl-11C]Propionyl-L-carnitine, given intravenously to rats, cleared rapidly from plasma. A slow uptake of radioactivity into myocardium and striated muscle was observed. In plasma, unchanged tracer represented 84% of the radioactivity at 2.5 min and 2.5% of the radioactivity at 60 min. In heart, unchanged tracer represented 18% of radioactivity at 2.5 min and 2.4% at 15 min. The remainder of radioactivity detected in plasma and heart was identified as [N-methyl-11C]L-carnitine and [N-methyl-11C]acetyl-L-carnitine.
    Nuclear Medicine and Biology 09/1995; 22(6):699-709. · 2.52 Impact Factor
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    ABSTRACT: The selective -HT1A receptor radioligand, [11C]WAY-100635 {[11C]N-2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridyl)cyclohexanecarboxamide}, has been injected intravenously into healthy male volunteers and studied by PET (positron emission tomography). The results provide the first delineation of 5-HT1A receptors in living human brain and demonstrate the potential to use [11C]WAY-100635 for the study of central 5-HT1A receptors in patients with psychiatric and neurological disorders and for the investigation of the pharmacology of drugs acting on the central nervous system.
    European Journal of Pharmacology - EUR J PHARMACOL. 01/1995; 283(1).
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    ABSTRACT: We describe a novel instrument which is capable of measuring the uptake of radioligand in human organs in vivo with the administration of very small doses of positron-emitting radioligands. This technique readily detects the displacement or reduced uptake of radioligand when a competitive agonist or antagonist is administered. This system provides no tomographic information, but the small radioactive doses involved mean that investigations can be repeated at regular intervals and that female volunteers can also participate. We administered [(11) C]flumazenil, [(11)C]diprenorphine, [(11)C]meta -hydroxyephedrine (MHED) and [(11)C]RTI 55 to healthy male volunteers and performed control, pre-loading and displacement experiments. These demonstrate the feasibility of using this technique to investigate benzodiazepine and opiate receptor occupancy, as well as occupancy at dopamine, noradrenaline and serotonin (5-HT) re-uptake sites. This method is likely to be useful in pharmacokinetic/pharmacodynamic experiments, in drug development and discovery and in the development of novel imaging radioligands.
    Journal of Psychopharmacology 01/1995; 9(4):294-306. · 3.37 Impact Factor