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V W Pike

Publications and source records attributed to V W Pike.

At least 55 records · Page 3Linked to original sources
PubMed1992

PET radioligands for dopamine receptors and re-uptake sites: chemistry and biochemistry.

This report, based on the past experience of European centres, offers practical guidance on the chemistry and biochemistry of PET radioligands used for the in vivo imaging of dopamine receptors and re-uptake sites. It mainly summarizes methods for the preparation of D1 and D2 receptor ligands labelled with positron-emitting radioisotopes. Some of these ligands (11C-labelled SCH23390, raclopride and nomifensine, 18F-labelled butyrophenones, [76Br]bromolisuride), which have been found useful in PET clinical investigations, have been emphasized. This report is intended as an introduction and guideline for new PET-groups who want to start research in the dopaminergic neurotransmission imaging field.

Animals↗
PubMed1992

Quantification of in vivo binding of [3H]RX 821002 in rat brain: evaluation as a radioligand for central alpha 2-adrenoceptors.

On the basis of its established in vitro characteristics, [3H]RX 821002 was evaluated in rats as an in vivo radioligand for central alpha 2-adrenoceptors. Estimates for in vivo binding potential, obtained by compartmental analyses of time-radioactivity data, ranged between 1.9 for hypothalamus and 0.2 for cerebellum, with a regional distribution in brain which was similar to that observed in vitro. Selectivity and specificity of the signal were checked by predosing with either the alpha 2-antagonists, idazoxan or yohimbine, the alpha 2-agonist, clonidine, or the alpha 1-antagonist, prazosin. Pretreatment of the rats with the selective neurotoxin, DSP-4, had no significant effect on [3H]RX 821002 binding, suggesting that the majority of labelled sites were situated post-junctionally. The studies indicate that [3H]RX 821002 can be used experimentally as an in vivo marker for central alpha 2-adrenoceptors. The size and rate of expression of the specific signal encourage the development and assessment of [11C]RX 821002 for clinical PET studies.

Adrenergic alpha-Antagonists↗
PubMed1992

Evaluation of S-[11C]citalopram as a radioligand for in vivo labelling of 5-hydroxytryptamine uptake sites.

The biologically active S-enantiomer of [N-methyl-11C]citalopram was evaluated as a radioligand for in vivo labelling of the 5-hydroxytryptamine uptake site in brain, using ex vivo tissue counting in rats and positron emission tomography in man. In rats, the maximal signal for total versus non-specific binding was approx. 2 at 60-120 min after radioligand injection. Subsequent studies in man failed to identify a specific signal over a 90 min scanning period, due to prolonged retention of non-specific label.

Animals↗
PubMed1992

Ligands and tracers for PET studies of the 5-HT system--current status.

The status of the radiochemical development and biological evaluation of radioligands and tracers for PET studies of the serotonergic system is reviewed, indicating those agents with present value and those with future potential. Practical recommendations are given for the preparation of two useful radioligands for PET studies of central 5-HT2 receptors, namely [18F]setoperone and [18F]altanserin. Though, it has not proved possible to recommend tracers or radioligands for the study of other aspects of serotonergic system, prospects for future radiochemical development are indicated, especially for developing radioligands for the 5-HT re-uptake site, and for the 5-HT1 and 5-HT3 receptors.

Animals↗
PubMed1991

Citalopram: labelling with carbon-11 and evaluation in rat as a potential radioligand for in vivo PET studies of 5-HT re-uptake sites.

In vivo autoradiography of [N-methyl-3H]citalopram in rat brain shows a differential regional localization which correlates with the localization of 5-HT re-uptake binding sites defined in vitro. A comparison of the biodistribution of [N-methyl-3H]citalopram over 2 h after i.v. injection in (1) control rats (2) rats pre-dosed with either citalopram or paroxetine and (3) rats chemically-lesioned with p-chloroamphetamine provides an estimate of specific binding relative to total binding in vivo. The ratio of binding in certain regions (e.g. cingulate) to binding in a reference tissue (e.g. cerebellum) at 30-120 min post injection is c. 1.4. In view of these results a method was developed for labelling citalopram with carbon-11 (t1/2 = 20.3 min, beta + = 99.8%) to provide a potential radioligand for studies using positron emission tomography. Thus, reaction of nca [11C]iodomethane, prepared from cyclotron-produced [11C]carbon dioxide, with norcitalopram in ethanol containing 2,2,6,6-tetramethyl-piperidine for 5 min at 95 degrees C gives crude [N-methyl-11C]citalopram in 60% radiochemical yield, decay-corrected. HPLC on silica gel provides radiochemically and chemically pure [N-methyl-11C]citalopram, as assessed by TLC, HPLC and MS. This product (isolated radiochemical yield, 49%) is easily formulated for i.v. injection. Up to 2 GBq of formulated product with a specific activity of c. 15 GBq/mumol have been prepared within 40 min from the end of radionuclide production. The described radiosynthesis has also been applied to give the single biologically active (+)-enantiomer of [N-methyl-11C]citalopram rather than the racemate. This product gives enhanced specific signal in the rat following i.v. injection, the ratio of uptake in regions of interest relative to cerebellum approaching 2 at 90 min.

Animals↗
PubMed1991

A method of studying pharmacokinetics in man at picomolar drug concentrations.

1. We describe a new method that enables the tissue kinetics of picomolar concentrations of drugs to be measured in man. The method is based on the administration of a drug, labelled with a short-lived positron-emitting radioisotope, such as carbon-11 (t1/2 = 20.4 min, beta + = 99.8%) or fluorine-18 (t1/2 = 109.8 min, beta + = 96.9%), which is then detected in vivo by an array of 10 large uncollimated sodium iodide scintillation detectors, arranged as five opposing pairs, with each pair collecting data over one major organ or region of the body. 2. To illustrate the scope of the new method we report the results of administering [O-methyl-11C]-diprenorphine, an established radioligand for central opiate (mu, kappa, and delta) receptors and L-6-[18F]-fluoro-DOPA, a marker for dopaminergic neurons. 3. Only 2-10 muCi (74-370 kBq) of radioactivity are used and, as a consequence of the high specific activities with which carbon-11 and fluorine-18 labelled compounds can be prepared, the method requires less than a nanomole of drug to be administered. In many cases, this amount of drug might be considered low enough to avoid any adverse biological effect. Furthermore repeat studies are possible in many without delivering unacceptable radiation burdens. 4. The high sensitivity realised for both radioactivity and mass suggests a mean for determining the human biodistribution of a new drug at a very early stage in its development. This has potential benefit to drug discovery programmes and to ensuing drug therapies.

Blood-Brain Barrier↗
PubMed1990

The radiosynthesis of [18F]PK 14105 as an alternative radioligand for peripheral type benzodiazepine binding sites.

A method has been developed for labelling PK 14105 [N-methyl-N-(1-methyl-propyl)-1(2-fluoro-5-nitrophenyl)isoquinoline-3- carboxamide], a ligand that has high affinity and selectivity for peripheral type benzodiazepine binding sites (PBBS), with NCA fluorine-18 (t1/2 = 109.8 min, beta + = 96.9%). The method involves treating the 2-chloro-analogue with cyclotron-produced NCA [18F]fluoride in dimethyl sulphoxide, with rubidium carbonate as base, at 140 degrees C for 20 min. Purification is achieved by separation on a reverse phase Sep-Pak followed by PHLC on a silica gel column, to give chemically and radiochemically pure product with a specific activity of ca 7.4 GBq/mumol (200 mCi/mumol), decay-corrected to the end of radionuclide production (EOB). The radiosynthesis requires 210 min. giving a radiochemical yield of 10-20%, decay-corrected to EOB. [18F]PK 14105 was found to bind avidly to sites associated with kainic acid-induced unilateral lesions of rat striata. Such binding was blocked by pre-dosing the rat with PK 11195, so providing evidence for specific binding to PBBS. These results suggest that [18F]PK 14105 has potential for studying phenomena associated with PBBS in man by PET.

Animals↗
PubMed1990

Labelled agents for PET studies of the dopaminergic system--some quality assurance methods, experience and issues.

Practical methods are described for the quality assurance of three labelled agents (L-6-[18F]fluoro-DOPA, S-[N-methyl-11C]nomifensine and [O-methyl-11C]raclopride) now produced regularly for PET studies of the dopaminergic system in man. These include indirect methods for the initial determination of label position (e.g. 13C-NMR spectroscopy) and also direct methods for the assessment of chiral purity (TLC and HPLC) and the routine determination of radiochemical purity, chemical purity and specific activity (HPLC). Mass spectrometry has been used to identify some impurities. L-6-hydroxy-DOPA (a precursor in vivo of the neurotoxin, L-6-hydroxydopamine) has been detected by HPLC in some preparations of L-6-[18F]fluoro-DOPA. Formulated S-[N-methyl-11C]nomifensine has been found to decrease in radiochemical purity with storage, whereas formulated [O-methyl-11C]raclopride has been found to be stable. Some quality assurance issues are discussed in relation to experience in the application of the described methods and the obtained results.

Carbon Radioisotopes↗
PubMed1989

The radiosynthesis of [N-methyl-11C]-sertraline.

[N-methyl-11C]Sertraline, a potential agent for the study of the serotonergic system in vivo with positron emission tomography, was prepared by N-methylation of the corresponding norcompound with [11C]iodomethane, which was itself prepared from cyclotron-produced [11C]carbon dioxide. Under the best conditions found [norsertraline free base (20 mM) in DMF (0.70 mL), 120 degrees C for 8 min] [N-methyl-11C]-sertraline can be prepared in 43% radiochemical yield from [11C]iodomethane (decay-corrected), corresponding to 20% overall radiochemical yield from [11C]carbon dioxide (decay-corrected), with high specific radioactivity. Preparations can be ready for i.v. injection 50 min from the end of radionuclide production.

1-Naphthylamine↗
PubMed1988

Regional cerebral opioid receptor studies with [11C]diprenorphine in normal volunteers.

The results are described of the cerebral uptake and heterogeneous retention of [11C]diprenorphine after intravenous injection in 4 normal volunteers. This potent opioid antagonist (Kd = 0.2 nM) was chosen because of its safety, lack of side-effects at trace doses in human pilot studies, rapid cerebral uptake and high percentage (80-90%) specific binding in animal in vivo studies. High uptake of [11C]diprenorphine was demonstrated in regions such as the thalamus, caudate nucleus, temporal, frontal and parietal cortices, which are known from postmortem studies to have high concentrations of opioid receptors. A stable level of activity or a very slow decline in activity was observed between 20 and 50 min after injection in areas such as the caudate nucleus and thalamus. Conversely, rapid washout of activity was observed in the occipital cortex, which is known to have low opioid receptor concentrations. Some 80-90% of maximum binding was naloxone reversible. These results with a ligand that is safe and without side-effects, suggest that this technique is suitable for studies of opioid physiology in man.

Brain↗
PubMed1988

Radiosynthesis of NCA [carbonyl-11C]6-fluoromelatonin.

A method is described for the preparation of [carbonyl-11C]6-fluoromelatonin for intravenous injection and potential study of the melatonin system in vivo by positron emission tomography. The preparation is based on the acetylation of 6-fluoro-5-methoxytryptamine with NCA [1-11C]acetyl chloride (itself prepared from cyclotron-produced [11C]carbon dioxide) and purification by HPLC. It gives chemically and radiochemically pure [carbonyl-11C]6-fluoromelatonin in 35% radiochemical yield (from [11C]CO2, decay-corrected) within 35 min from the end of radionuclide production and with high specific activity e.g. 1.6 GBq/mumol (43 mCi/mumol) at the end of synthesis from 1.1 GBq (30 mCi) of [11C]carbon dioxide.

Carbon Radioisotopes↗
PubMed1987

The preparation of a carbon-11 labelled neurohormone--[11C]melatonin.

Melatonin, a hormone of the pineal gland, has been labelled with the positron-emitting radionuclide, carbon-11 (t1/2 = 20.4 min), for study in vivo by positron emission tomography. Thus a novel labelling agent, [11C]acetyl chloride, was prepared by the carbonation of methylmagnesium bromide with cyclotron-produced [11C]carbon dioxide followed by treatment with phthaloyl dichloride. Acylation of 5-methoxytryptamine then affords [11C]melatonin, which is purified by HPLC and formulated for intravenous injection. The preparation requires 35 min from the end of radionuclide production. It provides [11C]melatonin in 13% radiochemical yield (decay-corrected from 11CO2) and in high specific activity. Radiochemical and chemical purity were demonstrated by HPLC and TLC. The validity of the radiosynthesis was also confirmed by a parallel synthesis of [13C]melatonin and examination of the product by 13C-NMR spectroscopy and mass spectrometry.

Carbon Dioxide↗
PubMed1987

Preparation of [11C]buprenorphine--a potential radioligand for the study of the opiate receptor system in vivo.

A method is described for the preparation of [11C]buprenorphine in high specific activity, based on the reaction of N-(de-cyclopropylmethyl)buprenorphine with "no carrier added" [1-11C]cyclopropanecarbonyl chloride followed by reduction with lithium aluminium hydride. The [1-11C]cyclopropanecarbonyl chloride is itself prepared from cyclotron-produced [11C]carbon dioxide. The overall preparation time is 57 min from the end of radionuclide production, and the radiochemical yield is ca 20%, (decay-corrected from [11C]-carbon dioxide). [11C]Buprenorphine has potential as a radioligand for the study of the opiate receptor system in vivo by means of position emission tomography.

Animals↗
PubMed1986

Regional myocardial and organ blood flow after myocardial infarction: application of the microsphere principle in man.

A physiologic means of measuring the distribution of cardiac output and regional myocardial blood flow has been developed that uses human albumin microspheres labeled with carbon-11 (11C) and external detection with positron emission tomography. Ten patients with previous myocardial infarction were studied to investigate the level of blood flow in normal and infarcted segments of the heart. After diagnostic catheterization, 4 to 6 mCi of 11C on 2 to 3 million sterile microspheres (15 to 20 micron) were mixed and injected into the apex of the left ventricle during timed withdrawal of arterial blood to obtain reference flow values. Regional activity in brain, heart, lungs, liver, spleen, and kidneys was measured tomographically. Blood flow was calculated based on the relationship between total activity in a reference flow and tissue activity in tomograms of each organ (ml/min/100 g). No adverse effects were noted after injection of the microspheres. Successive myocardial tomograms showed no loss of activity. There were no significant differences in flow values in matched regions of paired organs. Mean cerebral flow was 52.4 +/- 10.0 ml/min/100 g in the frontal lobes, 54.4 +/- 8.8 in the temporal lobes, 67.6 +/- 8.2 in the occipital lobes, and 53.0 +/- 9.4 in the basal ganglia. Flow was 16.0 +/- 8.4 ml/min/100 g (range 0 to 40.0) in the center of infarcted myocardium and 82.0 +/- 32.0 in the remote segments. This method meets most of the demands for use of microspheres to measure tissue blood flow. The wide range of flow values in infarcted myocardium may be a function of infarct size, spatial resolution, or pathologic evidence of islands of viable tissue. Patients with angina had high flow values in the infarcted segment, whereas those with heart failure had significantly lower values. Surviving myocardium in the region of the infarct may need to be considered if patients complain of angina, particularly when treatment is aimed at preserving ventricular function.

Adult↗
PubMed1984

Preparation of human serum [methyl-11C]methylalbumin microspheres and human serum [methyl-11C]methylalbumin for clinical use.

Safely-injectable suspensions of human serum [methyl-11 C] methylalbumin microspheres have been prepared via the reaction of human serum albumin microspheres with [11C]methyl iodide, itself prepared in a novel one-pot synthesis from cyclotron-produced [11C]carbon dioxide. The preparation takes only 30 min from the end of radionuclide production and proceeds in 22% radiochemical yield based on the activity of [11C]carbon dioxide used and decay-corrected. It has been shown that such microspheres are highly stable in vivo and may be used as reference blood flow markers in positron emission tomography (PET). Similarly, safely-injectable and radiochemically pure solutions of human serum [methyl-11C] methylalbumin have been prepared in 31% radiochemical yield and in 40 min from the end of [11C]carbon dioxide production via the reaction of [11C]methyl iodide with human serum albumin. This radiopharmaceutical is intended for studies of lung permeability and blood-brain barrier permeability by PET.

Animals↗
PubMed1984

Semi-automated preparation of a 11C-labelled antibiotic--[N-methyl-11C]erythromycin A lactobionate.

A fast semi-automated method is described for labeling the antibiotic, erythromycin A (1), with the short-lived positron-emitting radionuclide, 11C (t 1/2 = 20.4 min), in order to permit the non-invasive study of its tissue uptake in vivo. Labelling was achieved by the fast reductive methylation of N-demethylerythromycin A (2) with [11C]formaldehyde, itself prepared from cyclotron-produced [11C]-carbon dioxide. Rapid chemical and radiochemical purification of the [N-methyl-11C]erythromycin A (3) were achieved by HPLC and verified by TLC with autoradiography. The purified material was formulated for human i.v. injection as a sterile apyrogenic solution of the lactobionate salt. The preparation takes 42 min from the end of radionuclide production and from [11C]carbon dioxide produces [N-methyl-C11]erythromycin A lactobionate in 1-12% radiochemical yield, corrected for radioactive decay.

Carbon Radioisotopes↗