Biomedical subjects

M R Kilbourn

Publications and source records attributed to M R Kilbourn.

At least 91 records · Page 5Linked to original sources

PubMed1990

Mouse brain distribution of a carbon-11 labeled vesamicol derivative: presynaptic marker of cholinergic neurons.

The regional mouse brain distribution of a new carbon-11 labeled derivative of vesamicol, [11C]-5-(N-methylamino)benzovesamicol [( 11C]MABV) is reported. Radiotracer concentrations in vivo are in the rank order of striatum greater than cortex greater than hippocampus greater than hypothalamus greater than cerebellum, consistent with reported distributions of other presynaptic cholinergic neuronal markers. In time course studies, striatum/cerebellum and cortex/cerebellum ratios for (-)-[11C]MABV continue to increase to values of 13 and 5, respectively, 75 min after i.v. injection of [11C]MABV. The specific binding in striatum and cortex is lowered by pretreatment with (+/-)-vesamicol, and shows stereoselectivity with lower uptake and lower ratios for the (+)-enantiomer. (-)-enantiomer. (-)-[11C]MABV is proposed as a positron-emitting radioligand for the in vivo study of presynaptic cholinergic neurons.

Animals↗

PubMed1990

Extraction of [18F]fluoride from [18O]water by a fast fibrous anion exchange resin.

[18F]Fluoride for nucleophilic radiofluorination was recovered from target water by trapping on a fibrous anion exchange resin in the hydroxide form and subsequent displacement into wet methanolic K2CO3. Extraction into methanol facilitated rapid evaporation and resolubilization of the [18F]fluoride as an ion pair. The resin was first dried in situ and rehydrated with [18O]H2O to avoid isotopic dilution of the target water.

Anion Exchange Resins↗

PubMed1990

Synthesis of fluorine-18 labeled GABA uptake inhibitors.

The first syntheses of fluorine-18 labeled inhibitors of GABA reuptake [(R,S)-1-[2-[4-[18F]fluorophenyl]phenyl]methoxyethyl]piperidine- 3-carboxylic acid, (R,S)-1-[2-[(4-[18F]trifluoromethyl)phenyl][(4- trifluoromethyl)phenyl]-methoxyethyl]piperidine-3-carboxylic acid] are described. These N-substituted nipecotic acid derivatives were prepared in no-carrier-added form by the condensation of the appropriately substituted [18F]benzhydryl chlorides (prepared in three steps from [18F]fluoride ion) with N-(2-hydroxyethyl)nipecotic acid ethyl ester, followed by ester hydrolysis. Overall radiochemical yields were 17-28% (corrected, 150 min synthesis time). A simple new method for synthesis of a [18F]trifluoromethyl group by the nucleophilic substitution of a bromodifluoromethyl substituent has also been developed.

Fluorine Radioisotopes↗

PubMed1990

Direct simultaneous production of [15O]water and [13N]ammonia or [18F]fluoride ion by 26 MeV proton irradiation of a double chamber water target.

A simple double liquid chamber target was developed to provide the option for simultaneous production of [15O]H2O and either 13N or 18F using a single proton beam. Irradiation of natural water in a thin aluminium front chamber produced [15O]H2O by the 16O(p, pn)15O reaction directly. Large (0.5-1.0 Ci) doses of sterile [15O]H2O (greater than 99.95% radionuclide purity) were routinely prepared in 1 min from end of 20 microA bombardments using this target and an in-line mixed bed ion exchange column purification. Water in the thin front chamber degraded proton energies on exit to 20-18 MeV. The rear silver liquid chamber was threefold thick to 17 MeV protons in water and it efficiently produced either 13N by the 16O(p, alpha)13N reaction or [18F]fluoride ion by the 18O(p, n)18F reaction. Both target chambers were overpressurized with at least 6 atm of gas to minimize boiling/cavitation of water at high beam currents. Using hydrogen as the overpressure gas on the back chamber and an in-line anion exchange column radionuclidic cleanup process, high yields of sterile, aqueous [13N]NH3 (40-200 mCi; 20 microA) were produced directly from the back chamber at the same time that [15O]H2O was being produced from the front chamber. The combination of this target system with a cyclotron capable of generating 26-30 MeV protons provides great flexibility and simplicity for rapid, high volume production of the three best validated and most widely used radiopharmaceuticals at the present time in clinical positron emission tomography: [15O]H2O, [13N]NH3 and [18F]FDG.

Ammonia↗

PubMed1990

Routine production of 2-deoxy-2-[18F]fluoro-D-glucose by direct nucleophilic exchange on a quaternary 4-aminopyridinium resin.

Resin-supported [18F]fluoride ion has been prepared and applied to a rapid, convenient synthesis of [18F]FDG. "No-carrier-added" [18F]fluoride ion is collected on a quaternary 4-(N,N-dialkylamino)-pyridinium functionalized polystyrene anion exchange resin directly from a [18O]water target, dried by rinsing with acetonitrile, and then reacted with 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-beta-D-mann opyrannose. Acidic hydrolysis yields [18F]FDG in a synthesis time of 40 min with overall yields presently averaging above 50%.

Anion Exchange Resins↗

PubMed1990

Imaging the dopamine uptake site with ex vivo [18F]GBR 13119 binding autoradiography in rat brain.

We studied the binding of [18F]GBR 13119 (1-[[(4-[18F]fluorophenyl) (phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine) to rat brain with autoradiography after intravenous injection. The rank order of binding was dorsal striatum greater than nucleus accumbens = olfactory tubercle greater than substantia nigra = ventral tegmental area greater than other areas. Binding was blocked by prior injection of dopamine uptake blockers but not by injection of dopamine receptor antagonists or drugs that bind to the dialkylpiperazine site. Unilateral 6-hydroxy-dopamine lesions of dopamine neurons caused a marked decrease in striatal and nigral binding on the side of the lesion. We conclude that intravenous injection of [18F]GBR 13119 provides a useful marker of presynaptic dopamine uptake sites.

Animals↗

PubMed1989

Regional brain distribution of [18F]GBR 13119, a dopamine uptake inhibitor, in CD-1 and C57BL/6 mice.

We have examined the regional brain distribution of [18F]GBR 13119 (18F: beta +, T1/2 = 110 min), a dopamine uptake inhibitor, in CD-1 and C57BL/6 mice. High levels of binding are observed in the striatum of both species, with striatum/cerebellum ratios of 3-4 at 60 min after injection of the radiotracer. Striatum radioactivity and striatum/cerebellum ratios are more than 50% reduced in C57BL/6 mice treated chronically with the neurotoxin MPTP. We conclude mice are an appropriate model for the in vivo study of the dopamine uptake system, and that [18F]GBR 13119 may be a suitable in vivo marker for degeneration of striatal dopaminergic neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1989

PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site.

Human gliomas were imaged in vivo using ligands for the peripheral-type benzodiazepine binding site (or omega 3 binding site) and positron emission tomography (PET). Although gliomas have a high density of the peripheral-type benzodiazepine binding site, PET scans with a selective ligand for this site, [11C] Ro5-4864, failed to demonstrate higher radioactivity levels in human gliomas than in brain. In vitro studies of surgically removed specimens of human glioma demonstrated little binding of Ro5-4864 but high levels of binding of another selective ligand, PK 11195. Scans with [11C]PK 11195 demonstrated increased radioactivity in glioma compared to brain in 8 of 10 patients. Radioactivity in tumor and the ratios of radioactivity in tumor to that in remote gray and in white matter correlated significantly with the specific activity of [11C]PK 11195, suggesting that accumulation represents saturable high-affinity binding. We conclude that the PK 11195 manifests greater binding than Ro5-4864 to the peripheral-type benzodiazepine binding site on human gliomas and that human gliomas can be successfully imaged using [11C]PK 11195 and PET.

Benzodiazepinones↗

PubMed1989

Biodistribution, dosimetry, metabolism and monkey PET studies of [18F]GBR 13119. Imaging the dopamine uptake system in vivo.

The in vivo characteristics of a new radiotracer, [18F]GBR 13119, have been examined. Full body biodistribution in rats has been determined and the expected human dosimetry calculated. Pharmacological specificity of in vivo regional brain distribution in rats was examined. Blockage of specific binding was accomplished by dopamine reuptake inhibitors but no effect was observed for pretreatment with serotonin or norepinephrine reuptake inhibitors. Preliminary examination of rat blood shows the presence of radiolabeled metabolites, which can be rapidly identified using bonded-phase (Sep-Pak) chromatography. Finally, the striatum of living primates has been imaged using PET and i.v. administration of [18F]GBR 13119. These results represent the intermediate steps in the development of [18F]GBR 13119 as a radiotracer for the study of the dopamine uptake system in man.

Animals↗

PubMed1989

Thiophenes as phenyl bio-isosteres: application in radiopharmaceutical design--I. Dopamine uptake antagonists.

Possible applications of thiophenes in radiopharmaceutical chemistry have been explored. Thiophene for benzene ring substitution was applied to the synthesis of thienyl-[18F]GBR 13119, an analog of the potent and selective dopamine uptake inhibitor [18F]GBR 13119. In vivo regional brain distribution in mice shows essentially identical results for the thienyl and phenyl compounds (striatum/cerebellum ratios of greater than 4 at 60 min), suggesting successful substitution by the thiophene ring. The extension of this concept to the synthesis of no-carrier-added, high specific activity [18F]fluorothiophenes was examined: 5-[18F]fluoro-2-2-thiophene carboxaldehyde was prepared in 10-20% yields by an unprecedented [18F]fluoride-for-bromo substitution of 5-bromo-2-thiophenecarboxaldehyde. The possible advantages of thiophenes (lower log P, altered metabolism) in radiopharmaceutical chemistry are discussed.

Animals↗

PubMed1989

Synthesis and regional mouse brain distribution of [11C]nisoxetine, a norepinephrine uptake inhibitor.

Nisoxetine, a selective and high affinity (IC50 = 1 nM) inhibitor of NE reuptake, has been radiolabeled in high specific activity (greater than 600 Ci/mmol) by the alkylation of the nor-methyl precursor with [11C]CH3I. Synthetic yields are good (40-60% from [11C]methyl iodide, corrected for decay, 20 min synthesis), with the product purified by HPLC. In vivo studies of regional brain distribution in CD-1 mice show uptake and retention of tracer in the cortex, striatum, hypothalamus and thalamus, with the highest levels in the hypothalamus and cortex. Specific binding in the cortex and hypothalamus can be reduced by preadministration of 7 mg/kg i.v. unlabeled nisoxetine. The possible value of [11C]nisoxetine as a PET imaging agent is discussed.

Animals↗

PubMed1989

Non-steady-state measurement of in vivo receptor binding with positron emission tomography: "dose-response" analysis.

We previously developed a non-steady-state technique using positron emission tomography (PET) and the radioligand 18F-spiperone (18F-SP) for the measurement of in vivo radioligand-receptor binding in brain. The purpose of this investigation is to determine the sensitivity of this method to alterations in the apparent number of available specific binding sites. Nine studies were performed on the same baboon. The animal was pretreated with varying doses of unlabeled SP (15-600 micrograms) to compete for specific binding sites. The experimental procedure included measurement of regional cerebral blood flow, cerebral blood volume, and the protein binding of 18F-SP in arterial blood. At least 3.5 hr after pretreatment, no-carrier-added 18F-SP (containing less than 3 micrograms SP) was administered intravenously. Sequential PET scans and measurements of arterial-blood radioactivity due to radioligand and its labeled metabolites continued for 3 hr. A 3-compartment model representing the in vivo behavior of radioligand was used to analyze the data. As expected, we found that an index of binding called the combined forward rate constant (which equals the product of the apparent maximum number of available specific binding sites and the association rate constant of radioligand for receptor) declined with increasing dose of unlabeled SP. Other estimated variables including the dissociation rate constant did not change. This demonstrates that our non-steady-state method for estimating radioligand-receptor binding kinetics can detect a decrease in the apparent number of available specific binding sites. This is an important step in the validation of this in vivo receptor binding assay and its subsequent application.

Animals↗

PubMed1988

In vivo binding of [18F]GBR 13119 to the brain dopamine uptake system.

Regional rat brain uptake of [18F]GBR 13119, a high specific activity, positron-emitter labeled derivative of the potent dopamine uptake antagonist GBR 12935, is reported. Striatum to cerebellum ratios of 3 are obtained at 90 minutes post injection. Specific binding in striatum can be blocked by pretreatment with dopamine uptake system antagonists (mazindol, nomifensine) but not with receptor antagonists (spiperone, flupenthixol). [18F]GBR 13119 is proposed as a new positron-emitting radioligand for in vivo PET studies of the pre-synaptic dopamine uptake system.

Animals↗

PubMed1988

Multiphase extraction: rapid phase-transfer of [18F]fluoride ion for nucleophilic radiolabeling reactions.

In multiphase extraction [18F]fluoride ion for radiolabeling is recovered from target water by passage through a small column of microporous polymer impregnated with a lipophilic cryptand or quaternary ammonium salt. The 18O enriched water can be recovered for reuse. The [18F]fluoride ion-pair is eluted from the column by a small volume of acetonitrile or other organic solvent. Evaporation of the acetonitrile removes traces of water to yield a reactive ion pair for nucleophilic radiofluorination reactions. A wide range of ion-pairs based on K+ or NH+4 cryptands or quaternary ammonium salts can be employed. The method was applied to the synthesis of [18F]FDG.

Deoxyglucose↗

PubMed1988

Synthesis of [18F]GBR13119, a presynaptic dopamine uptake antagonist.

[18F]GBR13119 (1-[(4-[18F]fluorophenyl)-(phenyl)methoxy]ethyl-4-(3-phenylpropyl) piperazine) has been prepared in no carrier added form by a four-step synthesis from [18F]fluoride. Isolated yields are 7-10% (uncorrected) in a synthesis time of 120 min. The product is obtained in high specific activity (greater than 1000 Ci/mmol) and high radiochemical purity (greater than 99%) without chromatographic purification. Small amounts of chemical impurity, identified as the nitro-substituted analog by independent synthesis, can be removed by HPLC. [18F]GBR13119 is proposed as a new radiotracer for the presynaptic dopamine uptake system.

Dopamine Antagonists↗

PubMed1988

Automated production of several positron-emitting radiopharmaceuticals using a single laboratory robot.

A Zymate Laboratory Automation System (Zymark Corp.), previously set up for the automated synthesis of 16 alpha-[18F]fluoroestradiol-17 beta [Brodack et al. (1986a) J. Nucl. Med. 27, 714] has been modified for the production of several short-lived radiopharmaceuticals in a single hot cell. All manipulations and apparatus normally used in the syntheses of carbon-11 and fluorine-18-labeled radiopharmaceuticals have been incorporated into the robot system. This achievement permits facile modifications of existing procedures used by the robot in addition to the incorporation of new routines in a minimal amount of time. Currently, the Zymate robot is programmed for the routine production of 16 alpha-[18F]fluoroestradiol-17 beta (7-11% EOS in 80 min), N-(3-[18F]fluoropropyl)spiperone (15-18% EOS in 70 min), and [1-11C]butanol (11-15% EOS in 25 min). A fourth compound, 2-deoxy-2-[18F]fluoro-D-glucose, is also synthesized by the robot. The yields and synthesis times of the robot-produced compounds are comparable to those obtained during manual syntheses. This method of automation represents a flexible and versatile alternative for the routine production of radiopharmaceuticals used in PET studies.

Fluorine Radioisotopes↗

PubMed1988

Robotic production of 2-deoxy-2-[18F]fluoro-D-glucose: a routine method of synthesis using tetrabutylammonium [18F]fluoride.

Using existing robotic hardware and software programs developed for the synthesis of several positron-emitting radiopharmaceuticals for PET imaging [Brodack et al. (1988) Appl. Radiat. Isot. 39, 689], the additional automated synthesis of 2-deoxy-2-[18F]fluoro-D-glucose (2-[18F]FDG) has been incorporated into our Zymate Laboratory Automation System. The robotic synthesis of 2-[18F]FDG took less than one week to implement, including the organization of software subroutines and construction of an additional heating station. The end of synthesis yield (12-17%) and radiochemical purity (96-99%) for the robotic preparation of 2-[18F]FDG is similar to that of the manual synthesis. This automated method uses anhydrous tetrabutylammonium [18F]fluoride as the reactive fluoride source in the labeling step. The procedure is a modification of the synthesis reported by Hamacher et al. [Hamacher et al. (1986) J. Nucl. Med. 27, 235].

Deoxy Sugars↗

PubMed1988

A captive solvent method for rapid N-[11C]methylation of secondary amides: application to the benzodiazepine, 4'-chlorodiazepam (RO5-4864).

[11C]4'-Chlorodiazepam (RO5-4864), for PET studies of peripheral benzodiazepine receptors, was synthesized by alkylation of 1-desmethyl-4'-chlorodiazepam, in a small volume of acetone adsorbed on acrylic yarn, with [11C]methyl iodide in the injection loop of a liquid chromatograph. The reaction mixture was introduced directly onto a small, disposable alumina chromatographic column. Elution with pentane:ethanol gave a product of high chemical and radiochemical purity. A simple heating and cooling device for the injection loop is described.

Benzodiazepinones↗