ORCID Profile
0000-0001-8575-3703
Current Organisations
Aalborg Universitetshospital
,
Aalborg Universitet
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Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.BRAINRESBULL.2004.08.007
Abstract: The availability of dopamine D(2/3) binding sites in brain of six male and six female Göttingen minipigs was measured in a baseline condition and after challenge with hetamine sulfate (1mg/kg, i.v.) in PET studies with [(11)C]raclopride. Maps of the binding potential (pB B(max)/K(d)) of [(11)C]raclopride were spatially normalized and co-registered to a common stereotaxic coordinate system for pig brain. The pB maps were then analyzed by volume of interest and voxel-wise comparisons of gender and condition. The mean baseline pB tended to be 10-20% higher in striatum of the female group, but this gender difference was not significant. Variance of the mean baseline pB was higher in the males (44%) than in females (30%), but there was no correlation between pB and in idual plasma cortisol or testosterone concentrations. Using statistical parametric mapping, we detected a focus in the right posterior putamen where the magnitude of the hetamine-evoked decrease in pB was greater in the male than in the female group. Thus, the spatial pattern of reactivity of dopamine D(2/3) receptor availability to hetamine challenge is not identical in male and female pigs. Within the entire population, the decline in pB evoked by hetamine (Delta pB) was greater in the ventral striatum (-28%) than in the caudate nucleus (-17%), consistent with earlier reports in monkeys and humans. The magnitude of Delta pB correlated highly with the baseline pB values in all isions of the striatum. Based upon the principles of competitive binding, the slope of this empirical relationship, f(i), is equal to the fraction of [(11)C]raclopride binding sites sensitive to endogenous dopamine the magnitude of this fraction ranged from 0.29 in the caudate to 0.36 in the ventral striatum.
Publisher: Elsevier BV
Date: 05-2003
DOI: 10.1016/S0969-8051(02)00448-1
Abstract: The binding of radioligand agonists to dopamine receptors in living brain can be informative about the abundance of receptors which are coupled to intracellular second messenger systems. Therefore, we developed a radiosynthesis for the dopamine D(2,3) partial agonist (R)-N- [1-(11)C]n-propylnorapomorphine ([(11)C]NPA). The uptake of this tracer in brain of anesthetized Göttingen miniature pigs was recorded by positron emission tomography (PET) and analyzed by compartmental analysis using the metabolite-corrected arterial input, and using reference tissue methods. [(11)C]NPA had a blood-brain unidirectional clearance of approximately 0.35 ml g(-1) min(-1) and an apparent distribution volume of 6 ml g(-1) in cerebellum. The ligand had a binding potential of 1.5 in striatum, comparable to that reported previously for the receptor antagonist [(11)C]raclopride in the same strain of animals. Significant binding was detected in the hypophysis, thalamus, and medial forebrain bundle. The binding in striatum was of comparable magnitude in normal pigs and in pigs with a documented 50% dopamine depletion produced by MPTP-intoxication. Deep brain stimulation of the subthalamus was without conspicuous effect on the binding of [(11)C]NPA in vivo. Results of this preliminary study indicate that this tracer meets many requirements for assaying dopamine agonist binding sites by PET.
Publisher: Wiley
Date: 2004
DOI: 10.1002/SYN.20053
Abstract: Positron emission tomography (PET) studies with radiolabeled dopamine D2-like receptor ligands reveal d- hetamine-evoked increases in the competition from endogenous dopamine. However, the corresponding effects of methylenedioxymeth hetamine (MDMA, "Ecstasy"), which releases catecholamines and also serotonin, are unknown. Using PET, we measured the binding potentials (pBs) of the benzamide [11C]raclopride and the butyrophenone N-[11C]methylspiperone ([11C]NMSP) in brain of living pigs first in a baseline condition and at 45 and 165 min after infusion of (+/-)-MDMA-HCl (1 mg/kg, i.v.). Concomitant studies of cerebral blood flow did not reveal significant perfusion changes in the cerebellum reference region or in striatum, supporting the present use of reference tissue methods for the mapping of MDMA-evoked pB changes. Relative to the baseline pB of [11C]raclopride for dopamine D(2/3) receptors in striatum (pB = 1.5-2.2), MDMA-treatment reduced pB by 35% in the first posttreatment scan and by 22% in the second posttreatment scan, comparable to changes typically evoked by d- hetamine at a similar dose. In most previous studies, the in vivo binding of butyrophenones has been nearly insensitive to d- hetamine-evoked dopamine release. However, we found the baseline pB of [11C]NMSP for dopamine D2-like receptors in striatum (pB = 4-5) was decreased by 30% in the first post-MDMA scan and by 50% in the second post-MDMA scan, irrespective of assumptions about the extent of equilibrium binding attained during the 90-min-long PET recordings. Distinct properties of MDMA such as simultaneous release of dopamine and serotonin in brain may account for the present finding of progressive decline in the availability of [11C]NMSP binding sites in striatum.
Publisher: Wiley
Date: 2005
DOI: 10.1002/SYN.20141
Abstract: The psychoactive properties of the hallucinogen LSD have frequently been attributed to high affinity interactions with serotonin 5HT2 receptors in brain. Possible effects of LSD on dopamine D2/3 receptor availability have not previously been investigated in living brain. Therefore, we used PET to map the binding potential (pB) of [11C]raclopride in brain of three pigs, first in a baseline condition, and again at 1 and 4 h after administration of LSD (2.5 microg/kg, i.v.). There was a progressive treatment effect in striatum, where the pB was significantly reduced by 19% at 4 h after LSD administration. Concomitant maps of cerebral blood flow did not reveal significant changes in perfusion during this interval. Subsequent in vitro studies showed that LSD displaced [3H]raclopride (2 nM) from pig brain cryostat sections with an IC50 of 275 nM according to a one-site model. Fitting of a two-site model to the data suggested the presence of a component of the displacement curves with a subnanomolar IC50, comprising 20% of the total [3H]raclopride binding. In microdialysis experiments, LSD at similar and higher doses did not evoke changes in the interstitial concentration of dopamine or its acidic metabolites in rat striatum. Together, these results are consistent with a direct interaction between LSD and a portion of dopamine D2/3 receptors in pig brain, possibly contributing to the psychopharmacology of LSD.
Publisher: Wiley
Date: 2010
DOI: 10.1002/SYN.20706
Abstract: We earlier reported an anomalous 50% decrease in [(11)C]N-methylspiperone ([(11)C]NMSP) binding to dopamine D(2)-like receptors in living pig striatum after challenge with 3,4-methylenedioxymeth hetamine (MDMA, "Ecstasy"), suggesting either (1) a species peculiarity in the vulnerability of butyrophenone binding to competition from dopamine or (2) a novel consequence of synergistic actions of serotonin and dopamine at dopamine receptors. To distinguish these possibilities, we used microPET to test the vulnerability of [(11)C]NMSP binding in striatum of rats with unilateral telencephalic serotonin lesions, later verified by [(125)I]RTI-55 autoradiography. Baseline [(11)C]NMSP microPET recordings were followed by either saline or MDMA-HCl (4 mg/kg) injections (i.v.), and a second [(11)C]NMSP recording, culminating with injection of [(3)H]raclopride for autoradiography ex vivo. Neither MDMA-challenge nor serotonin lesion had any detectable effect on [(11)C]NMSP binding. In contrast, MDMA challenge increased receptor occupancy by [(3)H]raclopride ex vivo (relative to the B(max) in vitro) from 8% to 12%, and doubled the free ligand concentration in cerebral cortex, apparently by blocking hepatic CYP2D6. Assuming a single binding-site model, the increased [(3)H]raclopride binding indicated doubling of the apparent equilibrium dissociation constant in vivo (K(app) (d)), revealing a 2-fold increase in competition from endogenous dopamine at [(3)H]raclopride binding sites. The results favor hypothesis (1) that the remarkable vulnerability of [(11)C]NMSP binding in pig striatum to MDMA challenge does not generalize to the rodent.
Publisher: Wiley
Date: 23-05-2003
DOI: 10.1002/SYN.10222
Abstract: In vitro, the novel diazabicyclononane NS 4194 has several thousand-fold selectivity for blocking the transport into rat brain synaptosomes of [(3)H]-serotonin in comparison to [(3)H]-dopamine or [(3)H]-noradrenaline. We have prepared [(11)C]-NS 4194 in order to test its properties for PET imaging of brain serotonin transporters in comparison with the well-documented tracer [(11)C]-DASB. Both compounds had rapid clearance from blood to brain of living pigs. The apparent equilibrium distribution volumes in cerebellum were 35 ml g(-1) for [(11)C]-NS 4194 and 11 ml g(-1) for [(11)C]-DASB. Pretreatment of pigs with citalopram did not reduce the uptake of either tracer in cerebellum, validating the use of that tissue as a nonbinding reference tissue for kinetic analysis of specific binding. The binding potential (pB) calculated for [(11)C]-NS 4194 using arterial input models was close to 0.5 in the telencephalon, and was 60% displaced by citalopram. However, the reference tissue method of Lammertsma was unsuited to calculate pB for this tracer, apparently due to its excessive nonspecific binding. In contrast to the relatively homogeneous binding of [(11)C]-NS 4194, the pB of [(11)C]-DASB ranged from 0.6 in frontal cortex to 2 in the mesencephalon when calculated by the method of Lammertsma. Parametric maps of the pB of [(11)C]-DASB showed a pattern consistent with the known distribution of serotonin transporters in pig brain in vitro, and there was a uniform displacement of 80% of the specific binding after citalopram treatment in vivo. In conclusion, [(11)C]-DASB is in several respects superior to [(11)C]-NS 4194 for the detection of serotonin uptake sites by PET.
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.NEUROIMAGE.2006.11.038
Abstract: The performance of small animal PET for neuroreceptor studies in a psychopharmacological challenge paradigm is not yet well-described. Therefore, we used microPET and [(11)C]raclopride to map the availability of dopamine D(2/3) receptors in brain of anesthetized rats, first in a baseline condition, and again after challenge with saline or d- hetamine. Parametric maps of the specific binding (binding potential, pB) were calculated using a reference tissue input from cerebellum, and spatially normalized to a digitized stereotaxic coordinate system for rat brain. In volumes of interest (VOIs), the mean baseline pB (n=6) was 2.05 in dorsal striatum (caudate-putamen), and 1.34 in ventral striatum (nucleus accumbens), and did not significantly differ upon retest 2 h later. The availability of [(11)C]raclopride binding sites at baseline was 8% higher in the right striatum. Challenge with hetamine sulfate (1 mg/kg, i.v., n=4) decreased pB by 19% in both ventral and dorsal striatum. We have earlier predicted that blockade of monoamine oxidase (MAO) should potentiate the hetamine-evoked dopamine release, thus enhancing the displacement of [(11)C]raclopride binding in vivo. However, pretreatment of rats with pargyline hydrochloride (4 mg/kg, n=4 20 mg/kg, n=4) 1 day prior to PET did not potentiate the hetamine-evoked reduction in dopamine receptor availability within the extended striatum. We conclude that small animal PET can be used to investigate stimulant-induced dopamine release, but that the spatial resolution is insufficient to detect differences between relative changes in dorsal vs. ventral isions of the rat striatum. Furthermore, the present results do not reveal potentiation of the hetamine-evoked release of dopamine in rats with MAO inhibition.
Publisher: Elsevier BV
Date: 11-2005
DOI: 10.1016/J.BBR.2005.06.008
Abstract: Behavioral response to novelty in rats has been linked both to dopamine transmission in the ventral striatum, and to propensity to self-administer psychostimulant drugs. In order to probe the relationship between behavioral response to novelty and dopamine systems we have developed a behavioral model for correlation with positron emission tomography (PET) of dopamine transmission in brain of Göttingen minipigs. In the present study, we measured exploration of a novel object by recording the number of contacts, and duration of contact with a novel object, in groups of six male and six female adult minipigs. We hypothesized that these novelty scores would correlate with the hetamine-evoked dopamine release in ventral striatum, measured 2 weeks later in a PET study of the availability of binding sites for the dopamine D2/3 antagonist [11C]raclopride. There were significant correlations between duration of contact with a novel object and the hetamine-evoked reductions in binding potential (DeltapB) in the left ventral striatum of the 12 animals Comparison of results by gender revealed that the correlation was driven mainly by the male group, and was not present in the female group. We interpret these results to show that propensity to explore an unfamiliar object is relatively elevated in pigs with low basal occupancy of dopamine D2/3 receptors by endogenous dopamine, and with high hetamine-induced occupancy of released dopamine in the male pigs.
Publisher: Wiley
Date: 19-06-2018
DOI: 10.1002/JLCR.3640
Abstract: The development of bacteria-specific infection radiotracers is of considerable interest to improve diagnostic accuracy and enabling therapy monitoring. The aim of this study was to determine if the previously reported radiolabelled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA) conjugated peptide [
Publisher: Wiley
Date: 2007
DOI: 10.1002/SYN.20377
Abstract: The psychostimulant 3,4-methylendioxymeth hetamine (MDMA, "ecstasy") evokes degeneration of telencephalic serotonin innervations in rodents, nonhuman primates, and human recreational drug users. However, there has been no alternative to nonhuman primates for studies of the cognitive and neurochemical consequences of serotonin depletion in a large-bodied animal. Therefore, we used positron emission tomography (PET) with [(11)C]DASB to map the distribution of plasma membrane serotonin transporters in brain of Göttingen minipigs, first in a baseline condition, and again at 2 weeks after treatment with MDMA (i.m.), administered at a range of doses. In parallel PET studies, [(11)C]WAY-100635 was used to map the distribution of serotonin 5HT(1A) receptors. The acute MDMA treatment in awake pigs evoked 1 degrees C of hyperthermia. MDMA at total doses greater than 20 mg/kg administered over 2-4 days reduced the binding potential (pB) of [(11)C]DASB for serotonin transporters in porcine brain. A mean total dose of 42 mg/kg MDMA in four animals evoked a mean 32% decrease in [(11)C]DASB pB in mesencephalon and diencephalon, and a mean 53% decrease in telencephalic structures. However, this depletion of serotonin innervations was not associated with consistent alterations in the binding of [(11)C]WAY-100635 to serotonin 5HT(1A) receptors. Stereological cell counting of serotonin-positive neurons, which numbered 95,000 in the dorsal raphé nucleus of normal animals, was unaffected in MDMA-treated group. group.
Publisher: American Chemical Society (ACS)
Date: 29-02-2008
DOI: 10.1021/JM701378E
Abstract: ( R)-(-)- and ( S)-(+)-1-(1-[ (11)C]methyl-1 H-pyrrol-2-yl)-2-phenyl-2-(1-pyrrolidinyl)ethanone 4 and 5 were synthesized, and their properties as tracers for positron emission tomography (PET) studies of monoamine oxidase type A (MAO-A) in the brain of living pigs were tested. Parametric maps of the distribution volume ( V d) 4 in pig brain were qualitatively similar to those obtained with [ (11)C]harmine, with prominent binding in the ventral forebrain and mesencephalon. Its binding was highly vulnerable to MAO blockade, suggesting a binding potential as high as 2 for MAO-A sites. The slow plasma metabolism of 4 and 5 may present advantages over [ (11)C]harmine for routine PET studies of MAO-A.
Publisher: Wiley
Date: 2006
DOI: 10.1002/SYN.20258
Abstract: The activity of both isozymes of monoamine oxidase (MAO) is reduced by 50% in the brain of human smokers. We hypothesized that this is not an epiphenomenon, but should bring about potentiation of the action of psychostimulant drugs. To test this hypothesis, we carried out serial positron emission tomography (PET) studies in Göttingen miniature pigs to measure the binding of the MAO-A ligand [11C]harmine and to measure the changes in [11C]raclopride binding evoked by a low dose of hetamine (0.7 mg/kg as free base, i.v.), first in a baseline condition, and, one month later, after acute treatment with pargyline (2 x 3 mg/kg as free base, i.m.). In the baseline, the distribution volume of [11C]harmine relative to the arterial input (V(d), ml g(-1)) ranged from 74 ml g(-1) in cerebellum to 139 ml g(-1) in the medial hypothalamus. Pargyline treatment reduced the magnitude of V(d) globally to 34-54 ml g(-1). Nearly complete displacement of [11C]harmine binding was detected in neocortex and striatum, but there was evidence for pargyline-resistant binding in the pituitary gland and diencephalon. In the baseline condition, the low dose of hetamine evoked a 14% decline in the binding potential (BP) (pB) of [11C]raclopride in striatum (P = 0.026). After pargyline treatment, the hetamine effect was of similar magnitude (-11%), although not statistically significant (P = 0.054). However, the second hetamine challenge evoked a 24% reduction in [11C]raclopride pB relative to the original baseline condition (P = 0.018). Present results do not strongly support our hypothesis that MAO inhibition should potentiate the hetamine-evoked dopamine release as measured in the [11C]raclopride competition paradigm.
No related grants have been discovered for svend borup jensen.