Biomedical subjects

K J Fasth

Publications and source records attributed to K J Fasth.

At least 19 recordsLinked to original sources

PubMed2003

Demonstration of high monoaminoxidase-A levels in neuroendocrine gastroenteropancreatic tumors in vitro and in vivo-tumor visualization using positron emission tomography with 11C-harmine.

BACKGROUND AND AIMS: A majority of neuroendocrine gastroenteropancreatic (GEP) tumors can be detected by conventional radiological methods and scintigraphic techniques. Still there are problems to visualize small tumor lesions and non-functioning tumors. The aim of this study was to investigate some of the monoamine processing pathways of neuroendocrine GEP-tumors and try to find a new tracer substance for in vivo characterization and visualization by Positron Emission Tomography (PET). SUBJECTS AND METHODS: Autoradiography of tumor sections from 8 midgut carcinoids (MGC) and 8 endocrine pancreatic tumors (EPT) was performed with (11)C-labeled tracers for serotonin and dopamine transporters, serotonin HT2A-, dopamine D1- and muscarinic receptors and for monoamine oxidase A (MAO-A). The in vitro results initiated PET studies with (11)C-Harmine in 4 patients with MGC and 7 patients with EPT (one insulinoma, two glucagonomas and four non-functioning EPT). RESULTS: The MAO-A-ligand Harmine expressed specific in vitro binding of 87 +/-21% for MGC and 125 +/- 50% for EPT, compared to reference tissue (rat brain, 100%). All other substances showed relatively low specific binding. (11)C-harmine-PET could visualize tumors in all patients. The mean standardized uptake value (SUV) for MGC was 7.5 +/- 3.9 and for EPT 12.9 +/- 2.7, whereas the SUV of normal liver, intestine and pancreas were 3.1 +/- 0.5, 3.4 +/- 1.2 and 8.9 +/- 3.0 respectively. CONCLUSIONS: This study demonstrates in vitro and in vivo that neuroendocrine GEP-tumors are characterized by a high MAO-A-expression, thereby adding to the similarities of neuronal and neuroendocrine tissue. It also indicates a possible application for (11)C-harmine as a new PET-tracer for neuroendocrine GEP-tumors with the potential to visualize also non-functioning EPT's.

Biomarkers, Tumor↗

PubMed2001

Analysis of 76Br-BrdU in DNA of brain tumors after a PET study does not support its use as a proliferation marker.

76Br-bromodeoxyuridine has previously been suggested as a PET tracer to characterize proliferation potential. However, in animal studies a large fraction of the tissue radioactivity is due to 76Br-bromide, which remains extracellular for extensive periods and contributes significantly to the level of radioactivity. The present project aimed at investigating whether in human brain tumors, sufficient amounts of 76Br-bromodeoxyuridine would be incorporated into DNA, to motivate further attempts with this tracer. Eight patients with brain tumors: 3 meningiomas, 2 astrocytoma grade IV, 1 astrocytoma oligodendroglioma grade II-IV and 2 metastases, were examined with PET and 76Br-BrdU on three occasions: immediately after injection of the tracer, at 4-6, and at 18-20 hours after administration. After the first PET study, diuresis was introduced and maintained for about 12 hours. About 20 hours after tracer administration, 200 mg/m(2) bromodeoxyuridine was administered to 7 patients median 5.8 (range 1-22) hours prior to operation allowing the immunohistochemical analysis of the proliferation potential. During the operation, tumor samples were taken and radioactivity in DNA extracted and measured. The uptake of radioactivity was higher in the tumors than in brain parenchyma. However, in the operative samples only 1-27% (average: 9%) of the radioactivity was found in the DNA fraction. The plasma radioactivity remained high throughout the study with only minimal signs of elimination by the diuresis. 76Br-BrdU is extensively metabolized to 76Br-bromide, and only a minor fraction of the radioactivity is found in the DNA fraction, making it unlikely that this tracer can be used for assessment of proliferation potential.

Aged↗

PubMed2001

Middle cerebral artery occlusion and reperfusion in primates monitored by microdialysis and sequential positron emission tomography.

BACKGROUND AND PURPOSE: In a previous investigation concerning the hemodynamic and metabolic changes over time displayed by sequential positron emission tomography (PET) in a middle cerebral artery (MCA) occlusion/reperfusion primate model, a metabolic threshold for irreversible ischemia could be identified (reduction of metabolic rate of oxygen [CMRO(2)] to approximately 60% of the contralateral hemisphere). To evaluate the potential of microdialysis (MD) as an instrument for chemical brain monitoring, the aim of this subsequent study was to relate the chemical changes in MD levels directly to the regional metabolic status (CMRO(2) above or below the metabolic threshold) and the occurrence of reperfusion, as assessed by PET. METHODS: Continuous MD (2 probes in each brain) and sequential PET measurements were performed during MCA occlusion (2 hours) and 18 hours (mean) of reperfusion in 8 monkeys (Macaca mulatta). Energy-related metabolites (lactate, pyruvate, and hypoxanthine) and glutamate were analyzed. The MD probe regions were divided into 3 categories on the basis of whether CMRO(2) was below or above 60% of the contralateral region (metabolic threshold level) during MCA occlusion and whether reperfusion was obtained: severe ischemia with reperfusion (n=4), severe ischemia without reperfusion (n=4), and penumbra with reperfusion (n=5). RESULTS: The lactate/pyruvate ratio, hypoxanthine, and glutamate showed similar patterns. MD probe regions with severe ischemia and reperfusion and probe regions with severe ischemia and no reperfusion displayed high and broad peaks, respectively, during MCA occlusion, and the levels almost never decreased to baseline. Penumbra MD probe regions displayed only slight transient increases during MCA occlusion and returned to baseline. CONCLUSIONS: This experimental study of focal ischemia showed that the extracellular changes of energy-related metabolites and glutamate differed depending on the ischemic state of the brain during MCA occlusion and depending on whether reperfusion occurred. If MD proves to be beneficial in clinical practice, it appears important to observe relative changes over time.

Animals↗

PubMed2000

Brain uptake and receptor binding of two [11C]labelled selective high affinity NK1-antagonists, GR203040 and GR205171--PET studies in rhesus monkey.

Two high affinity and selective NK1-receptor antagonists, GR203040 and GR205171, were labelled with 11C and used in a series of experiments in rhesus monkeys. The purpose of these studies was to evaluate the brain uptake pattern and to explore the potential use of these compounds as PET ligands to characterise NK1-receptor binding. Seventeen studies were carried out with [11C]GR205171 and five experiments with [11C]GR203040, including baseline studies and studies performed after a 5 min infusion of cold compound at doses between 0.05 and 1 mg/kg. Both compounds demonstrated a significant and rapid uptake in the brain, but the uptake of [11C]GR205171 was more than double the uptake of [11C]GR203040. At tracer doses of [11C]GR205171 and all doses of [11C]GR203040 the uptake reached a plateau with no washout during the examination time, whereas [11C]GR205171 after pre-treatment with cold GR205171 showed a significant washout. Using a model with the cerebellum as reference, a method for quantitation was applied to the studies with [11C]GR205171 and the results indicated that the highest specific binding was in the striatum. The pre-treatment dose of cold GR205171 needed for 50% inhibition of binding was less than 0.04 mg/kg. The studies indicated that [11C]GR205171 could be used for the in vivo characterisation of NK1-receptor binding.

Animals↗

PubMed2000

Synthesis of [76Br]bromofluorodeoxyuridine and its validation with regard to uptake, DNA incorporation, and excretion modulation in rats.

UNLABELLED: This investigation aimed to validate 5-[76Br]bromo-2'-fluoro-2'-deoxyuridine (BFU) as a proliferation marker using PET. METHODS: Five megabecquerels 76Br-BFU were injected into the tail vein of Sprague-Dawley rats. At 6 or 16 h after injection, the rats were killed and the radioactivity concentration was measured in 6 different organs and blood. The fraction of radioactivity incorporated into DNA was determined for the spleen and small intestine. In parallel experiments, the animals were pretreated with hydroxyurea. In a few experiments, the urinary excretion of radioactivity was measured from administration of 76Br-BFU until 6 h. A sample of urine was analyzed with HPLC. In separate experiments, rats were given different doses of cimetidine, and the organ uptake and the fraction of radioactivity in DNA were determined at 24 h. RESULTS: The highest organ uptake of radioactivity was found in the spleen, followed by the small intestine. Approximately 90% of the radioactivity in these organs was incorporated into DNA, and inhibition by hydroxyurea was pronounced. Intact tracer constituted more than 95% of the radioactivity in urine. With cimetidine, the uptake of radioactivity increased approximately 2-5 times at different doses, whereas the urine radioactivity decreased markedly. CONCLUSION: 76Br-BFU was predominantly incorporated into DNA after administration in vivo in rats. If cimetidine was given in combination with the tracer, an increased contrast of radioactivity concentration between organs of high proliferation and organs of low proliferation was observed. The investigation suggested that 76Br-BFU has good potential as a PET tracer for the assessment of proliferation in vivo.

Animals↗

PubMed1999

Absorption of L-DOPA from the proximal small intestine studied in the rhesus monkey by positron emission tomography.

Positron emission tomography (PET) seems to be a valuable method for the understanding of intestinal absorption mechanisms, for simultaneous quantitation of absorption rate and distribution kinetics to the tissues of interest after oral drug delivery. PET was evaluated in three Rhesus monkeys for quantitation of the absorption rate from the gastrointestinal tract and the distribution kinetics into different organs. To obtain optimal standardized conditions for the measurement of absorption the drug was administered via a naso-duodenal catheter directly to the absorption site in the proximal small intestine. l-DOPA was used as study drug given in a suspension together with carbidopa and the radiomarker l-[beta-11C]DOPA. The l-DOPA suspension was given into the duodenum without and after administration of a suspension of six l-amino acids (120 mM) in order to investigate any interaction on the intestinal absorption and distribution of l-DOPA into the liver and brain tissue. Intestinal absorption was in general minor during the first study period and higher together with administered l-amino acids. The somewhat contradictory result with increased absorption when amino acids were present in the intestinal lumen, may be a consequence of increased intestinal motility initiated by the nutrient load.

Animals↗

PubMed1999

In vivo positron emission tomography studies on the novel nicotinic receptor agonist [11C]MPA compared with [11C]ABT-418 and (S)(-)[11C]nicotine in rhesus monkeys.

The novel 11C-labeled nicotinic agonist (R,S)-1-[11C]methyl-2(3-pyridyl)azetidine ([11C]MPA) was evaluated as a positron emission tomography (PET) ligand for in vivo characterization of nicotinic acetylcholine receptors in the brain of Rhesus monkeys in comparison with the nicotinic ligands (S)-3-methyl-5-(1-[11C]methyl-2-pyrrolidinyl)isoxazol ([11C]ABT-418) and (S)(-)[11C]nicotine. The nicotinic receptor agonist [11C]MPA demonstrated rapid uptake into the brain to a similar extent as (S)(-) [11C]nicotine and [11C]ABT-418. When unlabeled (S)(-)nicotine (0.02 mg/kg) was administered 5 min before the radioactive tracers, the uptake of [11C]MPA was decreased by 25% in the thalamus, 19% in the temporal cortex, and 11% in the cerebellum, whereas an increase was found for the uptake of (S)(-)[11C]nicotine and [11C]ABT-418. This finding indicates specific binding of [11C]MPA to nicotinic receptors in the brain in a simple classical displacement study. [11C]MPA seems to be a more promising radiotracer than (S)(-)[11C]nicotine or [11C]ABT-418 for PET studies to characterize nicotinic receptors in the brain.

Animals↗

PubMed1999

Elimination of nonspecific radioactivity from [76Br]bromide in PET study with [76Br]bromodeoxyuridine.

[76Br]Bromodeoxyuridine ([76Br]BrdU) might allow a determination of proliferation in vivo using positron emission tomography (PET), but only with consideration of organ nonspecific radioactivity constituted by [76Br]bromide. A first study assessed the potential of diuretics to eliminate [76Br]bromide. [76Br]Bromide was injected in the vein of rats and different diuretic combinations were given. Urine was collected and radioactivity measured. Torasemide plus sodium chloride gave better 76Br elimination than the other diuretics. In a second experiment, rats were given [76Br]BrdU. After the radioactivity injection, the rats of the treatment group were given torasemide plus NaCl. At 44 h after the radioactivity injection, the radioactivity concentration and the fraction incorporated into DNA were measured in different organs. Using diuretics, the elimination of [76Br]bromide was increased. The radioactivity decreased 30-50% in most of the organs but the highest radioactivity uptake was found in the organs with more active DNA synthesis. This method may facilitate the use of [76Br]BrdU as a tracer for DNA synthesis using PET.

Animals↗

PubMed1999

Synthesis and characterization of binding of 5-[76Br]bromo-3-[[2(S)-azetidinyl]methoxy]pyridine, a novel nicotinic acetylcholine receptor ligand, in rat brain.

5-[76Br]Bromo-3-[[2(S)-azetidinyl]methoxy]pyridine ([76Br]BAP), a novel nicotinic acetylcholine receptor ligand, was synthesized using [76Br]bromide in an oxidative bromodestannylation of the corresponding trimethylstannyl compound. The radiochemical yield was 25%, and the specific radioactivity was on the order of 1 Ci/micromol. The binding properties of [76Br]BAP were characterized in vitro and in vivo in rat brain, and positron emission tomography (PET) experiments were performed in two rhesus monkeys. In association experiments on membranes of the cortex and thalamus, >90% of maximal specific [76Br]BAP binding was obtained after 60 min. The dissociation half-life of [76Br]BAP was 51 +/- 6 min in cortical membranes and 56 +/- 3 min in thalamic membranes. Saturation experiments with [76Br]BAP revealed one population of binding sites with dissociation constant (K(D)) values of 36 +/- 9 and 30 +/- 9 pM in membranes of cortex and thalamus, respectively. The maximal binding site density (Bmax) values were 90 +/- 17 and 207 +/- 33 fmol/mg in membranes of cortex and thalamus, respectively. Scatchard plots were nonlinear, and the Hill coefficients were <1, suggesting the presence of a lower-affinity binding site. In vitro autoradiography studies showed that binding of [76Br]BAP was high in the thalamus and presubiculum, moderate in the cortex and striatum, and low in the cerebellum and hippocampus. A similar pattern of [76Br]BAP accumulation was observed by ex vivo autoradiography. In vivo, binding of [76Br]BAP in whole rat brain was blocked by preinjection of (S)(-)-nicotine (0.3 mg/kg) by 27, 52, 68, and 91% at survival times of 10, 25, 40, 120, and 300 min, respectively. In a preliminary PET study in rhesus monkeys, the highest [76Br]BAP uptake was found in the thalamus, and radioactivity was displaceable by approximately 60% with cytisine and by 50% with (S)(-)-nicotine. The data of this study indicate that [76Br]BAP is a promising radioligand for the characterization of nicotinic acetylcholine receptors in vivo.

Alkaloids↗

PubMed1999

A comparison of 11C-labeled L-DOPA and L-fluorodopa as positron emission tomography tracers for the presynaptic dopaminergic system.

11C-labeled 3,4-Dihydroxy-phenyl-L-alanine (L-DOPA) and L-fluorodopa were used as tracers for the functional state of the presynaptic dopamine system in anesthetized monkeys with positron emission tomography. The radiotracer disposition in brain tissue and plasma were studied and effects induced by pharmacologic challenges were evaluated. 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) increased the striatal influx rate constant, e.g., striatal K(i) for L-[beta-11C]DOPA, but it induced no effect on the K(i)-value using L-[beta-11C]-6-fluorodopa. Studies of radiolabeled tracer and metabolites in plasma showed substantial differences between the two tracers. At baseline conditions, 60% unchanged L-[beta-11C]DOPA was detected in plasma 50 minutes after tracer injection and the 3-O-methylated fraction accounted for 25% of total radioactivity. For L-[beta-11C]-6-fluorodopa, the relation was inverse; about 25% unchanged tracer and 60% 3-O-methyl metabolite were present in plasma after 50 minutes. A site-specific 11C-labeling in the carboxylic position in the molecules revealed a significant specific retention of radioactivity in striatum with L-[car-boxy-11C]-6-fluorodopa but not with L-[carboxy-11C]DOPA. The 3-O-methyl metabolite of L-DOPA is known to pass the blood-brain barrier and may interfere with the calculation of the K(i)value using a brain reference region. Thus, extensive 3-O-methylation in circulation of the fluorinated analog could obscure the detectability of potential functional change in striatal K(i) of the tracer when using a reference tissue model for calculation.

Animals↗

PubMed1998

Effects of the substituted (S)-3-phenylpiperidine (-)-OSU6162 on PET measurements in subhuman primates: evidence for tone-dependent normalization of striatal dopaminergic activity.

(-)-OSU6162 is a substituted (S)-3-phenylpiperidine derivative which exhibits some affinity to the dopamine D2 receptor family. In vivo, the compound displays a unique normalizing profile on psychomotor activity by an intriguing mixture of stimulatory and inhibitory properties. In the present investigation, some of the effects of (-)-OSU6162 on central dopaminergic function were studied by positron emission tomography (PET) and L-[11C]DOPA in anaesthetized female rhesus monkeys. (-)-OSU6162 displayed a dopaminergic tone-dependent effect with a reduction in the striatal L-[11C]DOPA influx rate in monkeys with high baseline values and an increased striatal L-[11C]DOPA influx rate in animals with low baseline values. Infusion of (-)-OSU6162 for a whole day resulted in a stable effect with no evidence of tolerance. (-)-OSU6162 also stabilized dopaminergic function by attenuating the upregulation of the striatal L-[11C]DOPA influx rate which has previously been shown to occur following 6R-BH4 or 6R-BH4 + L-tyrosine infusions. This "Protean" effect of (-)-OSU6162 on the striatal dopaminergic function corresponds to previous behavioral observations in intact animals and demonstrates a true functional correlation to the measures obtained with L-[11C]DOPA and PET. The normalizing and stabilizing profile of (-)-OSU6162 should be of value in treating a variety of disorders where an underlying dysregulation or disruption of dopaminergic function can be assumed.

Animals↗

PubMed1998

In vitro evaluation of 11C-labeled (S)-nicotine, (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole, and (R,S)-1-methyl-2-(3-pyridyl)azetidine as nicotinic receptor ligands for positron emission tomography studies.

The binding characteristics of the novel 11C-labeled nicotinic ligands (R,S)-1-methyl-2-(3-pyridyl) azetidine (MPA) and (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT-418) were investigated in comparison with those of (S)-[11C]nicotine in vitro in the rat brain to be able to predict the binding properties of the new ligands for positron emission tomography studies in vivo. The data from time-resolved experiments for all ligands indicated fast binding kinetics, with the exception of a slower dissociation of [11C]MPA in comparison with (S)-[11C]nicotine and [11C]ABT-418. Saturation experiments revealed for all ligands two nicotinic receptor binding sites with affinity constants (K(D) values) of 2.4 and 560 nM and binding site densities (Bmax values) of 65.5 and 223 fmol/mg of protein for (S)-[11C]nicotine, K(D) values of 0.011 and 2.2 nM and Bmax values of 4.4 and 70.7 fmol/mg of protein for [11C]MPA, and K(D) values of 1.3 and 33.4 nM and Bmax values of 8.8 and 69.2 fmol/mg of protein for [11C]ABT-418. In competing with the 11C-ligands, epibatidine was most potent, followed by cytisine. A different rank order of potencies was found for (-)-nicotine, (+)-nicotine, MPA, and ABT-418 displacing each of the 11C-ligands. Autoradiograms displayed a similar pattern of receptor binding for all ligands, whereby [11C]MPA showed the most distinct binding pattern and the lowest nonspecific binding. We conclude that the three 11C-labeled nicotinic ligands were suitable for characterizing nicotinic receptors in vitro. The very high affinity of [11C]MPA to nicotinic acetylcholine receptors, its low nonspecific binding, and especially the slower dissociation kinetics of the [11C] MPA from the putative high-affinity nicotinic acetylcholine receptor binding site compared with (S)-[11C]nicotine and [11C]ABT-418 raise the level of interest in [11C]MPAfor application in positron emission tomography.

Animals↗

PubMed1998

Brain networks affected by synchronized sleep visualized by positron emission tomography.

Nineteen lightly sleep-deprived healthy volunteers were examined with H2(15)O and positron emission tomography (PET). Scanning was performed during wakefulness and after the subjects had fallen asleep. Sleep stage was graded retrospectively from electroencephalogram (EEG) recordings, and scans were divided into two groups: wakefulness or synchronized sleep. Global flow was quantified, revealing no difference between sleep and wakefulness. A pixel-by-pixel-blocked one-way analysis of variance (ANOVA) was performed after correcting for differences in anatomy and global flow. The sum of squares of the z-score distribution showed a highly significant (P < 0.00001) omnibus difference between sleep and wakefulness. The z-score images indicated decreased flow in the thalamus and the frontal and parietal association cortices and increased flow in the cerebellum during sleep. A principal component (PC) analysis was performed on data after correction for global flow and block effects, and a multivariate analysis of variance (MANOVA) on all PC scores revealed significant (P = 0.00004) differences between sleep and wakefulness. Principal component's 2 and 5 correlated to sleep and revealed distinct networks consisting of PC 2, cerebellum and frontal and parietal association cortices, and PC 5, thalamus.

Analysis of Variance↗

PubMed1998

In vitro and animal validation of bromine-76-bromodeoxyuridine as a proliferation marker.

UNLABELLED: The potential of 76Br-bromodeoxyuridine as a PET tracer for characterizing proliferation potential was investigated in multicellular tumor aggregates and in healthy rats and pigs. METHODS: Bromine-76-bromide was produced by proton irradiation of a 76Se-enriched target using a 17-MeV cyclotron and recovered by thermal diffusion. Bromine-76-BrdU was prepared from the corresponding trimethylstannate by an oxidative bromination. Multicellular aggregates from a carcinoid cell line and two bladder cancer cell lines were co-incubated with 76Br-BrdU and 3H-thymidine and the uptake and DNA incorporation analyzed. About 0.5 MBq 76Br-BrdU were injected in the tail vein of unanaesthetised Sprague-Dawley rats. Two to 36 hr later they were decapitated and the radioactivity concentration and fraction of radioactivity incorporated into DNA determined in five different organs and the blood. Parallel studies were performed in animals pretreated with hydroxyurea. In separate experiments, rats were given an injection of 76Br-bromide and organ uptake was evaluated after 20 hr. PET studies were performed in two pigs and the uptake in different organs was investigated after injection of 76Br-BrdU. In these studies, diuresis was induced by furosemide and mannitol and radioactivity in blood and organs was followed during 10 hr. RESULTS: In the cell aggregates, 30%-90% of the radioactivity was extracted in the DNA fraction. A good correlation was found between 76Br-BrdU and 3H-thymidine with respect to total uptake and DNA fraction. The DNA fraction increased from 2-10 hr after incubation. With in vivo injection in the rat, relatively high uptake of radioactivity was found in all organs, unrelated to the degree of DNA synthesis. However, inhibition by hydroxyurea occurred only in the spleen and intestines, organs which also showed a high degree of incorporation of 76Br-BrdU into DNA. In the pig, the highest in vivo uptake was observed in the red bone marrow and the intestines. In these organs, 70%-80% of the radioactivity was recovered in the DNA fraction. The concentration of radioactivity in the heart, liver and kidney was 3-10 times lower, and here the DNA fraction accounted for 10%-20% of the radioactivity. The decay-corrected radioactivity in blood and nonproliferating organs decreased with diuresis with a half-life of 13 and 16 hr, respectively. CONCLUSION: It is suggested that the radioactivity uptake as seen after the administration of 76Br-BrdU, is constituted by two parts: one relating to incorporation into DNA and one existing as free 76Br- or metabolites of 76Br-BrdU. If sufficient time has passed, 76Br- dominates other metabolites. A correct assessment of DNA-incorporated radioactivity using PET with 76Br-BrdU is not trivial and can only be made with due correction for 76Br-, using either a complementary investigation after hydroxyurea pretreatment (in animal studies) or a separate 76Br-bromide investigation. Alternatively, the free bromide can be eliminated partially through forced diuresis.

Animals↗

PubMed1997

Amphetamine effects on dopamine release and synthesis rate studied in the Rhesus monkey brain by positron emission tomography.

Positron emission tomography (PET) was used in a multitracer protocol to evaluate D-amphetamine induced effects on dopamine biosynthesis rate and release in propofol anesthetized Rhesus monkeys. L-[beta-11C]DOPA was used as biochemical probe to study the brain dopamine biosynthesis rate whilst dopamine release was followed by the binding displacement of the [11C]-radiolabelled dopamine receptor antagonists, raclopride and N-methylspiperone. Studies were performed with either a constant rate intravenous infusion of D-amphetamine aiming at plasma concentrations of 0.2 to 25 ng/ml or with intravenous bolus doses of 0.1 and 0.4 mg/kg. Decreased binding of the dopamine receptor antagonists was measured in both modes of D-amphetamine administration but notably [11C]N-methylspiperone was less able to sense D-amphetamine induced release of dopamine. At plasma concentrations aimed above 1 ng/ml a levelling off of the binding of [11C]raclopride at 68 +/- 8.1% of the baseline value indicated that displacement was only possible from a fraction of the binding sites. Amphetamine was observed to increase the rate constant for L-[beta-11C]DOPA utilization in the brain. This was most likely due to an acutely induced subsensitivity of presynaptic dopamine receptors. L-[beta-11C]DOPA and [11C]raclopride were found suitable to indicate changes in dopamine synthesis rate and release respectively using PET and can be used to mirror drug-induced changes of brain dopaminergic function.

Amphetamine↗

PubMed1997

Modulation of organ uptake of 11C-labelled L-DOPA.

The present study was undertaken to investigate if pretreatment with pharmacological agents could change the organ uptake of 11C-labelled L-DOPA, and especially if the urinary excretion could be decreased. L-[beta-11C]DOPA was injected IV into unanesthetized Sprague-Dawley rats. After 20 min the rats were decapitated and organs taken out for radioactivity measurements. The uptake in the organs was investigated in animals only given the tracer, and in animals pretreated with drugs such as decarboxylase inhibitors carbidopa and benserazide as well as the monoamine oxidase inhibitors deprenyl, clorgyline, and the COMT inhibitor OR-486. A marked decrease in the urinary radioactivity was observed after carbidopa and benserazide administration. HPLC analysis revealed that under native conditions the major part of urinary radioactivity existed as dopamine, which was eliminated by the decarboxylase inhibitors. After pretreatment with the COMT inhibitor OR-486, the radioactivity uptake in the pancreas increased fourfold as compared to non-treated animals. HPLC analysis showed that this correlated with a marked increase in radiolabelled DOPAC. In the other organs and with the other drugs, only small effects were observed. With L-[beta-11C]fluoroDOPA as a tracer, similar results were observed although the increase in the pancreas by OR-486 had a lower magnitude. These studies suggest that it might be possible to improve the diagnostic ratio of L-[beta-11C]DOPA or L-[18F]fluoroDOPA in whole-body PET studies by pretreating the patient with decarboxylase inhibitor for reducing the urinary excretion and potentially increase the target organ uptake by COMT inhibition.

Animals↗

PubMed1997

Synthesis of [11C-methyl]-(-)-OSU6162, its regional brain distribution and some pharmacological effects of (-)-OSU6162 on the dopaminergic system studied in the rhesus monkey by positron emission tomography.

The labelling of the presynaptic dopamine receptor antagonist (-)-OSU6162, ((S)-(-)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine) was performed by an alkylation with [11C]methyl iodide of the thio anion (-)-OSU1281, followed by a selective oxidation to the corresponding methyl sulfone, [11C-methyl]-(-)-OSU6162. The total radiochemical yield calculated from the produced [11C]carbon dioxide to final product was about 25% and the time of synthesis was in the range of 40 min from end of bombardment. The synthesis of the precursor, (-)-OSU1281, was performed from (-)-3PPP in a three-step synthesis. The regional brain distribution of (-)-OSU6162 radiolabelled with 11C was studied in rhesus monkeys by means of positron emission tomography, PET. [11C-Methyl]-(-)-OSU6162 was rapidly and uniformly distributed to gray matters of the brain, and no decrease of radioactivity uptake in the brain was seen after pretreatment with 1 to 3 mg/kg/h of (-)-OSU6162. The effect of doses of 1 to 3 mg/kg/h of (-)-OSU6162 on the dopamine binding was studied by PET using [11C-methyl]raclopride. Radioactivity in the striatum was significantly and dose-dependently decreased by (-)-OSU6162 (r = 0.88), supporting competition with dopamine for selective binding to dopamine receptors.

Animals↗

PubMed1997

Methodological aspects for in vitro characterization of receptor binding using 11C-labeled receptor ligands: a detailed study with the benzodiazepine receptor antagonist [11C]Ro 15-1788.

As a complement to in vivo studies with positron emission tomography (PET), it is desirable to perform in vitro characterization of newly developed 11C tracers. In this report we describe the technique for determination of receptor-ligand kinetics utilizing ligands labeled with the short-lived radionuclide 11C. The limitations and advantages are discussed. The benzodiazepine antagonist [11C]Ro 15-1788 was used as a model substance, and the use of storage phosphor plates for quantification of radioactivity was validated. Storage phosphor plates showed an excellent linear range (approximately 10[3]) and acceptable resolution (approximately 0.5 mm). Receptor-ligand kinetics, including depletion, association and dissociation, saturation and displacement were evaluated with good results through the use of short-lived radiotracers and storage phosphor plates.

Animals↗