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Kai Kendziorra,
Henrike Wolf,
Philipp Mael Meyer,
Henryk Barthel,
Swen Hesse,
Georg Alexander Becker,
Julia Luthardt,
Andreas Schildan,
Marianne Patt, Dietlind Sorger,
Anita Seese,
Herman-Josef Gertz,
Osama Sabri
[show abstract]
[hide abstract]
ABSTRACT: PurposePostmortem studies indicate a loss of nicotinic acetylcholine receptor (nAChRs) in Alzheimer’s disease (AD). In order to establish
whether these changes in the cholinergic system occur at an early stage of AD, we carried out positron emission tomography
(PET) with a specific radioligand for the α4β2* nicotinic acetylcholine receptor (α4β2* nAChR) in patients with mild to moderate
AD and in patients with amnestic mild cognitive impairment (MCI), who have a high risk to progress to AD.
MethodsNine patients with moderate AD, eight patients with MCI and seven age-matched healthy controls underwent 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BPND) of 2-[18F]FA-85380 was calculated using either the corpus callosum or the cerebellum as reference regions. PET data were analysed
by region of interest analysis and by voxel-based analysis.
ResultsBoth patients with AD and MCI showed a significant reduction in 2-[18F]FA-85380 BPND in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region.
The 2-[18F]FA-85380 BPND correlated with the severity of cognitive impairment. Only MCI patients that converted to AD in the later course (n = 5) had a reduction in 2-[18F]FA-85380 BPND.
Conclusion2-[18F]FA-85380 PET appears to be a sensitive and feasible tool for the detection of a reduction in α4β2* nAChRs which seems to
be an early event in AD. In addition, 2-[18F]FA-85380 PET might give prognostic information about a conversion from MCI to AD.
KeywordsNicotinic acetylcholine receptors–2-[18F]FA-85380–Alzheimer’s disease–MCI–PET
European journal of nuclear medicine and molecular imaging 05/2012; 38(3):515-525. · 4.99 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: This Letter describes the synthesis of two regioisomers of a new class of vesamicol analogs as possible ligands for imaging the vesicular acetylcholine transporter in future PET studies. The two pyrrolovesamicols (±)-6a and (±)-6b were synthesized by nucleophilic ring opening reaction of a tetrahydroindole epoxide precursor with 4-phenylpiperidine. The reaction mechanism of the synthesis was studied by HPLC and the molecular structures were determined by X-ray structure analysis. Unexpected low binding affinities to VAChT (K(i)=312±73 nM for (±)-6a and K(i)=7320±1840 nM for (±)-6b) were determined by competitive binding analysis using a cell line stably transfected with ratVAChT and (-)-[(3)H]vesamicol.
Bioorganic & medicinal chemistry letters 03/2012; 22(6):2163-6. · 2.65 Impact Factor
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Swen Hesse,
Peter Brust,
Peter Mäding,
Georg-Alexander Becker,
Marianne Patt,
Anita Seese, Dietlind Sorger,
Jörg Zessin,
Philipp M Meyer,
Donald Lobsien,
Sven Laudi,
Bernd Habermann,
Frank Füchtner,
Julia Luthardt,
Anke Bresch,
Jörg Steinbach,
Osama Sabri
[show abstract]
[hide abstract]
ABSTRACT: [(11)C]DASB is currently the most frequently used highly selective radiotracer for visualization and quantification of central SERT. Its use, however, is hampered by the short half-life of (11)C, the moderate cortical test-retest reliability, and the lack of quantifying endogenous serotonin. Labelling with (18)F allows in principle longer acquisition times for kinetic analysis in brain tissue and may provide higher sensitivity. The aim of our study was to firstly use the new highly SERT-selective (18)F-labelled fluoromethyl analogue of (+)-McN5652 ((+)-[(18)F]FMe-McN5652) in humans and to evaluate its potential for SERT quantification.
The PET data from five healthy volunteers (three men, two women, age 39 ± 10 years) coregistered with individual MRI scans were semiquantitatively assessed by volume-of-interest analysis using the software package PMOD. Rate constants and total distribution volumes (V (T)) were calculated using a two-tissue compartment model and arterial input function measurements were corrected for metabolite/plasma data. Standardized uptake region-to-cerebellum ratios as a measure of specific radiotracer accumulation were compared with those of a [(11)C]DASB PET dataset from 21 healthy subjects (10 men, 11 women, age 38 ± 8 years).
The two-tissue compartment model provided adequate fits to the data. Estimates of total distribution volume (V (T)) demonstrated good identifiability based on the coefficients of variation (COV) for the volumes of interest in SERT-rich and cortical areas (COV V (T) <10%). Compared with [(11)C]DASB PET, there was a tendency to lower mean uptake values in (+)-[(18)F]FMe-McN5652 PET; however, the standard deviation was also somewhat lower. Altogether, cerebral (+)-[(18)F]FMe-McN5652 uptake corresponded well with the known SERT distribution in humans.
The results showed that (+)-[(18)F]FMe-McN5652 is also suitable for in vivo quantification of SERT with PET. Because of the long half-life of (18)F, the widespread use within a satellite concept seems feasible.
European Journal of Nuclear Medicine 02/2012; 39(6):1001-11. · 4.53 Impact Factor
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Journal of Labelled Compounds 05/2011; 54(8):426 - 432.
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Kai Kendziorra,
Henrike Wolf,
Philipp Mael Meyer,
Henryk Barthel,
Swen Hesse,
Georg Alexander Becker,
Julia Luthardt,
Andreas Schildan,
Marianne Patt, Dietlind Sorger,
Anita Seese,
Herman-Josef Gertz,
Osama Sabri
[show abstract]
[hide abstract]
ABSTRACT: Postmortem studies indicate a loss of nicotinic acetylcholine receptor (nAChRs) in Alzheimer's disease (AD). In order to establish whether these changes in the cholinergic system occur at an early stage of AD, we carried out positron emission tomography (PET) with a specific radioligand for the α4β2* nicotinic acetylcholine receptor (α4β2* nAChR) in patients with mild to moderate AD and in patients with amnestic mild cognitive impairment (MCI), who have a high risk to progress to AD.
Nine patients with moderate AD, eight patients with MCI and seven age-matched healthy controls underwent 2-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[(18)F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BP(ND)) of 2-[(18)F]FA-85380 was calculated using either the corpus callosum or the cerebellum as reference regions. PET data were analysed by region of interest analysis and by voxel-based analysis.
Both patients with AD and MCI showed a significant reduction in 2-[(18)F]FA-85380 BP(ND) in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region. The 2-[(18)F]FA-85380 BP(ND) correlated with the severity of cognitive impairment. Only MCI patients that converted to AD in the later course (n = 5) had a reduction in 2-[(18)F]FA-85380 BP(ND).
2-[(18)F]FA-85380 PET appears to be a sensitive and feasible tool for the detection of a reduction in α4β2* nAChRs which seems to be an early event in AD. In addition, 2-[(18)F]FA-85380 PET might give prognostic information about a conversion from MCI to AD.
European Journal of Nuclear Medicine 11/2010; 38(3):515-25. · 4.53 Impact Factor
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Philipp M Meyer,
Karl Strecker,
Kai Kendziorra,
Georg Becker,
Swen Hesse,
Dominique Woelpl,
Anke Hensel,
Marianne Patt, Dietlind Sorger,
Florian Wegner,
Donald Lobsien,
Henryk Barthel,
Peter Brust,
Hermann J Gertz,
Osama Sabri,
Johannes Schwarz
[show abstract]
[hide abstract]
ABSTRACT: Cognitive or depressive disorders are frequently noted in patients with Parkinson disease (PD) and may be related to altered signaling through alpha4beta2*-nicotinic acetylcholine receptors (alpha4beta2*-nAChRs).
To assess the availability of alpha4beta2*-nAChRs and their relationship to mild cognitive and mild depressive symptoms in vivo in patients with PD.
Crossover comparison between patients with PD and healthy volunteers (control group) using the alpha4beta2*-nAChR-specific radioligand 2-[(18)F]fluoro-3-(2[S]-2-azetidinylmethoxy)-pyridine (2-[(18)F]FA-85380) and positron emission tomography.
Departments of Neurology and Nuclear Medicine, University of Leipzig, Leipzig, Germany.
Twenty-two nonsmoking patients with PD and 9 nonsmoking healthy volunteers.
Level of 2-[(18)F]FA-85380 binding potential (2-FA BP), a measure of alpha4beta2*-nAChR availability. The relationship between severity of cognitive symptoms as rated using the Mini-Mental State Examination and DemTect scale and the level of depressive symptoms as indicated using the Beck Depression Inventory, and 2-FA BP were assessed.
In patients with PD compared with healthy volunteers, there was widespread reduced 2-FA BP, especially in the midbrain, pons, anterior cingulate cortex, frontoparietal cortex, and cerebellum. In subgroups of patients with PD with possible depression, reduced 2-FA BP was most pronounced in the cingulate cortex and frontoparieto-occipital cortex, whereas in patients with PD with mild cognitive impairment, 2-FA BP was reduced in the midbrain, pons, and cerebellum. In patients with PD, the strongest associations between depressive symptoms and reduced 2-FA BP were noted in the anterior cingulate cortex, putamen, midbrain, and occipital cortex. In contrast, cognitive symptoms correlated only weakly with reduced 2-FA BP in the thalamus, midbrain, temporal cortex, hippocampus, and cerebellum.
There is a broad reduction of alpha4beta2*-nAChR availability in patients with PD without clinically manifest dementia or depression compared with healthy volunteers. Reduced alpha4beta2*-nAChR binding in patients with PD within the subcortical and cortical regions is associated with the severity of mild cognitive or depressive symptoms. These results provide novel in vivo evidence for a role of the cholinergic neurotransmission in psychiatric comorbidity of PD.
Archives of general psychiatry 09/2009; 66(8):866-77. · 12.26 Impact Factor
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Dietlind Sorger,
Matthias Scheunemann,
Johnny Vercouillie,
Udo Grossmann,
Steffen Fischer,
Achim Hiller,
Barbara Wenzel,
Ali Roghani,
Reinhard Schliebs,
Jörg Steinbach,
Peter Brust,
Osama Sabri
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[hide abstract]
ABSTRACT: Phenylpiperidinyl-octahydro-benzo[1,4]oxazines represent a new class of conformationally restrained vesamicol analogues. Derived from this morpholine-fused vesamicol structure, a new fluorine-18-labeled 4-fluorobenzoyl derivative ([(18)F]FBMV) was synthesized with an average specific activity of 75 GBq/micromol and a radiochemical purity of 99%. The radiolabeling method included an exchange reaction of a 4-nitro group of the precursor by fluorine-18, a reduction procedure to eliminate excess of the nitro compound, followed by a high-performance liquid chromatography purification. [(18)F]FBMV demonstrates (i) a moderate lipophilic character with a logD(pH7.0) 1.8+/-0.10; (ii) a considerable binding affinity to the vesicular acetylcholine transporter (VAChT) (K(i)=27.5 nM), as determined using PC12 cells transfected with a VAChT cDNA, and a low affinity to sigma(1,2) receptors (K(i) >3000 nM); (iii) a good uptake into the rat and pig brains; (iv) a typical accumulation in the VAChT-containing brain regions; and (v) an approximately 20% reduction in cortical tracer binding after a specific cholinergic lesion using 192IgG-saporin. [(18)F]FBMV exhibits another PET marker within the group of vesamicol derivatives that demonstrates potentials in imaging brain cholinergic deficits, while its usefulness in clinical practice must await further investigation.
Nuclear Medicine and Biology 01/2009; 36(1):17-27. · 3.02 Impact Factor
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Peter Brust,
Jörg Thomas Patt,
Winnie Deuther-Conrad,
Georg Becker,
Marianne Patt,
Andreas Schildan, Dietlind Sorger,
Kai Kendziorra,
Philipp Meyer,
Jörg Steinbach,
Osama Sabri
[show abstract]
[hide abstract]
ABSTRACT: Functional changes of nicotinic acetylcholine receptors (nAChR) are important during age-related neuronal degeneration. Recent studies demonstrate the applicability of the nAChR ligand 2-[(18)F]F-A-85380 for neuroimaging of patients with dementias. However, its binding kinetics demands a 7-h acquisition time limiting its practicality for clinical PET studies. Thus, the authors developed [(18)F]norchloro-fluoro-homoepibatidine ([(18)F]NCFHEB) for nAChR imaging. The kinetics of the two enantiomers of [(18)F]NCFHEB were compared with 2-[(18)F]F-A85380 in porcine brain to evaluate their potential for human neuroimaging. Twenty-four juvenile female pigs were studied with PET using [(18)F]NCFHEB. Nine animals received an additional i.v. injection (1 mg/kg) of the nAChR agonist A81418 before radiotracer administration followed by infusion (2 mg/kg/7h) thereafter. Several compartment models were applied for quantification. (-)- and (+)-[(18)F]NCFHEB showed a twofold to threefold higher brain uptake than 2-[(18)F]F-A-85380. All three radiotracers displayed spatially heterogeneous binding kinetics in regions with high, moderate, or low specific binding. The equilibrium of specific binding of (-)-[(18)F]NCFHEB was reached earlier than that of (+)-[(18)F]NCFHEB or 2-[(18)F]F-A85380. Continuous administration of the nAChR agonist A81418 inhibited the specific binding of (-)- and (+)-[(18)F]NCFHEB but not of 2-[(18)F]F-A85380. The peripheral metabolism of (+)-[(18)F]NCFHEB proceeded somewhat slower than that of the other radiotracers. Both enantiomers of [(18)F]NCFHEB are appropriate radiotracers for neuroimaging of nAChR in pigs. Their binding profile in vivo appears to be more selective than that of 2-[(18)F]F-A85380. (-)-[(18)F]NCFHEB offers a faster equilibrium of specific binding than 2-[(18)F]F-A85380.
Synapse 04/2008; 62(3):205-18. · 2.94 Impact Factor
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Dietlind Sorger,
Matthias Scheunemann,
Udo Grossmann,
Steffen Fischer,
Johnny Vercouille,
Achim Hiller,
Barbara Wenzel,
Ali Roghani,
Reinhard Schliebs,
Peter Brust,
Osama Sabri,
Jörg Steinbach
[show abstract]
[hide abstract]
ABSTRACT: With the aim of producing selective radiotracers for in vivo imaging of the vesicular acetylcholine transporter (VAChT) using positron mission tomography (PET), here, we report synthesis and analysis of a new class of conformationally constrained vesamicol analogues with moderate lipophilicity. The sequential ring opening on trans-1,4-cyclohexadiene dioxide enabled an approach to synthesize 6-arylpiperidino-octahydrobenzo[1,4]oxazine-7-ols [morpholino vesamicols]. The radiosynthesis of the [18F]fluoroacetyl-substituted derivative ([18F]FAMV) was achieved starting from a corresponding bromo precursor [2-Bromo-1-[7-hydroxy-6-(4-phenyl-piperidin-1-yl)-octahydro-benzo[1,4]oxazin-4-yl]-ethanone] and using a modified commercial computer-controlled module system with a radiochemical yield of 27+/-4%, a high radiochemical purity (99%) and a specific activity of 35 GBq/micromol. In competitive binding assays using a PC12 cell line overexpressing VAChT and [3H]-(-) vesamicol, 2-fluoro-1-[7-hydroxy-6-(4-phenyl-piperidin-1-yl)-octahydro-benzo[1,4]oxazin-4-yl]-ethanone (FAMV) demonstrated a high selectivity for binding to VAChT (K(i): 39.9+/-5.9 nM) when compared to its binding to sigma 1/2 receptors (Ki>1500 nM). The compound showed a moderate lipophilicity (logD (pH 7)=1.9) and a plasma protein binding of 49%. The brain uptake of [18F]FAMV was about 0.1% injected dose per gram at 5 min after injection and decreased continuously with time. Notably, an increasing accumulation of radioactivity in the lateral brain ventricles was observed. After 1 h, the accumulation of [18F]FAMV, expressed as ratio to the cerebellum, was 4.5 for the striatum, 2.0 for the cortical and 1.5 for the hippocampal regions, measured on brain slices using ex vivo autoradiography. At the present time, 75% of [18F]FAMV in the plasma was shown to be metabolized to various hydrophilic compounds, as detected by high-performance liquid chromatography. The degradation of [18F]FAMV was also detected in brain extracts as early as 15 min post injection (p.i.) and increased to 50% at 1 h postinjection. In conclusion, although the chemical properties of [18F]FAMV and the selectivity of binding to VAChT appear to be promising indicators of a useful PET tracer for imaging VAChT, a low brain extraction, in combination with only moderate specific accumulation in cholinergic brain regions and an insufficient in vivo stability prevents the application of this compound for neuroimaging in humans.
Nuclear Medicine and Biology 02/2008; 35(2):185-95. · 3.02 Impact Factor
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Dietlind Sorger,
Georg A Becker,
Marianne Patt,
Andreas Schildan,
Udo Grossmann,
Reinhard Schliebs,
Anita Seese,
Kai Kendziorra,
Magnus Kluge,
Peter Brust,
Alexey G Mukhin,
Osama Sabri
[show abstract]
[hide abstract]
ABSTRACT: 2-[(18)F]fluoro-A-85380 (2-[(18)F]FA) is a new radioligand for noninvasive imaging of alpha4beta2* nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET) in human brain. In most cases, quantification of 2-[(18)F]FA receptor binding involves measurement of free nonmetabolized radioligand concentration in blood. This requires an efficient and reliable method to separate radioactive metabolites from the parent compound. In the present study, three analytical methods, thin layer chromatography (TLC), high-performance liquid chromatography (HPLC) and solid phase extraction (SPE) have been tested. Reversed-phase TLC of deproteinized aqueous samples of plasma provides good estimates of 2-[(18)F]FA and its metabolites. However, because of the decreased radioactivity in plasma samples, this method can be used in humans over the first 2 h after radioligand injection only. Reliable quantification of the parent radioligand and its main metabolites was obtained using reversed-phase HPLC, followed by counting of eluted fractions in a well gamma counter. Three main and five minor metabolites of 2-[(18)F]FA were detected in human blood using this method. On average, the unchanged 2-[(18)F]FA fraction in plasma of healthy volunteers measured at 14, 60, 120, 240 and 420 min after radioligand injection was 87.3+/-2.2%, 74.4+/-3%, 68.8+/-5%, 62.3+/-8% and 61.0+/-8%, respectively. In patients with neurodegenerative disorders, the values corresponding to the three last time points were significantly lower. The fraction of nonmetabolized 2-[(18)F]FA in plasma determined using SPE did not differ significantly from that obtained by HPLC (+gamma counting) (n=73, r=.95). Since SPE is less time-consuming than HPLC and provides comparable results, we conclude that SPE appears to be the most suitable method for measurement of 2-[(18)F]FA parent fraction during PET investigations.
Nuclear Medicine and Biology 05/2007; 34(3):331-42. · 3.02 Impact Factor
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Dietlind Sorger,
Georg Alexander Becker,
Katharina Hauber,
Andreas Schildan,
Marianne Patt,
Gerd Birkenmeier,
Andreas Otto,
Philipp Meyer,
Magnus Kluge,
Reinhard Schliebs,
Osama Sabri
[show abstract]
[hide abstract]
ABSTRACT: To determine the availability of nicotinic acetylcholine receptors in different human brain regions using the positron emission tomography (PET) radioligand 2-[18F]fluoro-A-85380 (2-[18F]FA) and invasive approaches for quantification, it is important to correct the arterial input function as well for plasma protein binding (PPB) of the radioligand as for radiolabeled metabolites accumulating in blood. This study deals with some aspects of PPB of 2-[18F]FA.
Patients with different neurological disorders (n=72), such as Parkinson's disease, Alzheimer's disease and multiple sclerosis, and a group of healthy volunteers (n=15) subjected for PET imaging were analyzed for their PPB level of 2-[18F]FA using ultrafiltration. Protein gel electrophoresis of plasma samples was performed to identify the binding protein of 2-[18F]FA. The dependency of PPB on time and on free ligand concentration was analyzed to obtain the binding parameters Bmax and Kd.
Albumin was identified to be the binding protein of 2-[18F]FA. PPB of 2-[18F]FA was low at 17+/-4% and did not show significant differences between the groups of patients. Corresponding to this, a narrow range of plasma albumin of 0.62+/-0.05 mM was observed. Bmax was determined as twice the albumin concentration, which indicates two binding sites for 2-[18F]FA on the protein. No time dependence of the PPB could be observed. By relating PPB to Bmax, an average Kd value of 6.0+/-1.5 mM was obtained.
This study shows the dependency of PPB of 2-[18F]FA on human albumin plasma concentration. An equation utilizing Bmax and Kd to easily estimate PPB is presented.
Nuclear Medicine and Biology 11/2006; 33(7):899-906. · 3.02 Impact Factor
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[show abstract]
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ABSTRACT: 18F labelled vesamicol analogues, which bind to the vesicular acetylcholine transporter (VAChT) in central cholinergic nerve terminals, are expected to be potential radioligands for the visualisation of cholinergic transmission deficits via positron emission tomography (PET). In this report the regioselective synthesis of five novel vesamicol analogues as well as their in vitro binding properties to the VAChT are described. Beside having the 4-fluorobenzylether-substitution at the cyclohexyl ring as an unique structural feature, the new compounds are additionally modified at the phenyl and piperidine moiety of the vesamicol skeleton. The affinity and selectivity to the VAChT were analysed by competitive binding studies using tritium labelled radioligands. The VAChT affinities (Ki-values) of the novel compounds were estimated ranging between 7.8+/-3.5 nM and 161.6+/-17.3 nM, thus some of them are binding with higher affinity to the transporter than vesamicol. However, the compounds tested demonstrated also affinities to the sigma receptors sigma1 and sigma2 ranging between 4.1+/-1.5 nM and 327.5+/-75.9 nM. Nevertheless, these data provide the basis for future structure-binding-studies and further underline the potential and usefulness of vesamicol analogues for imaging of the VAChT.
European Journal of Medicinal Chemistry 01/2006; 40(12):1197-205. · 3.35 Impact Factor
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Philipp Meyer,
Donald Lobsien,
Kai Kendziorra,
Henryk Barthel,
Swen Hesse,
Georg Becker,
Andreas Schildan,
Marianne Patt, Dietlind Sorger,
Anita Seese,
Annette Foerschler,
Florian Then Bergh,
Peter Brust,
J|[ouml]|rg Steinbach,
Hermann-Josef Gertz,
Johannes Schwarz,
Claus Zimmer,
Osama Sabri
Journal of Cerebral Blood Flow & Metabolism 07/2005; · 5.01 Impact Factor
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ABSTRACT: Detection of the central cholinergic deficits, a consistent feature of Alzheimer's disease, is essential to allow preventive measures and/or symptomatic treatment already at a very early stage of the disease. The vesicular acetylcholine transporter (VAChT) represents an appropriate target to establish PET radiotracer that are adequate for brain imaging the loss of cholinergic terminals. Here we describe the synthesis and binding characteristics of novel derivatives of vesamicol, known to represent a specific antagonist of VAChT sites. Novel benzyl ether derivatives of vesamicol either 4- or 5-substituted at the cyclohexylring have been synthesized by different regioselective ring opening reactions of a same epoxide precursor. The affinity and selectivity of the novel compounds to VAChT sites were analyzed by competitive radioligand binding studies in rat brain and liver membrane preparations using tritium labeled radioligands. The 4-substituted fluorobenzylether of vesamicol 10b was shown to exhibit a high affinity to VAChT sites (K(i)-value(10b)=10.7+/-1.7 nM), but demonstrated also binding capacities to sigma receptors (K(i-)value(10b)=18.5+/-6.9 nM, [(3)H]DTG; K(i)-value(10b)=30.6+/-9.6 nM, [(3)H]haloperidol). The data suggest the potential of vesamicol derivatives to design appropriate radiotracer for PET imaging of central cholinergic deficits.
Bioorganic & Medicinal Chemistry 04/2004; 12(6):1459-65. · 2.92 Impact Factor
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ABSTRACT: Cholinergic deficits in Alzheimer's disease are accompanied by a number of alterations in other transmitter systems including glutamate, noradrenaline and serotonin, suggesting the involvement also of other neurotransmitter systems in the pathogenesis of the disease. To address the question whether beta-amyloid may contribute to these deficits, brain tissue from transgenic Tg2576 mice with Alzheimer plaque pathology at ages of 5 (still no significant plaque load) and 17 months (moderate to high cortical beta-amyloid plaque load) were examined for a number of cholinergic and non-cholinergic markers. Transgenic mice with no significant plaque load demonstrated reduced hemicholinium-3 (HCh-3) binding to choline uptake sites in anterior brain regions as compared to non-transgenic littermates, while in aged transgenic mice with high number of plaque deposits decreased HCh-3 binding levels were accompanied by increased vesicular acetylcholine transporter binding in selected cortical brain regions. In aged transgenic mice GABA(A), NMDA, AMPA, kainate, and beta-adrenergic as well 5-HT(1A)- and 5-HT(2A)-receptor binding levels were hardly affected, whereas alpha(1)- and alpha(2)-adrenoceptor binding was increased in selected cerebral cortical regions as compared to non-transgenic littermates. The development of changes in both cholinergic and non-cholinergic markers in transgenic Tg2576 mouse brain already before the onset of progressive plaque deposition provides in vivo evidence of a modulatory role of soluble beta-amyloid on cortical neurotransmission and may be referred to the deficits in learning and memory observed in these mice also before significant plaque load.
International Journal of Developmental Neuroscience 12/2003; 21(7):357-69. · 2.42 Impact Factor
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European Journal of Pediatrics 10/2003; 162(9):639-41. · 1.88 Impact Factor
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ABSTRACT: Pathological crying (PC) is a neuropsychiatric disorder characterized by an excessive tendency towards crying after brain damage. To elucidate the role of serotonin neurotransmission for PC, a pilot study was performed using single photon emission computed tomography with [123I]beta-CIT to estimate central (midbrain/pons and thalamus/hypothalamus) serotonin transporter (SERT) densities in 15 stroke patients who did or did not have PC. SERT binding ratios in midbrain/pons were significantly lower in the PC subgroup.
Psychiatry Research 08/2003; 123(3):207-11. · 2.52 Impact Factor
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ABSTRACT: The present study compares the uptake of [(18)F]Fluoroazomycinarabinofuranoside ((18)FAZA), a recently developed hypoxia tracer for PET imaging of tissue hypoxia, with an established tracer [(18)F]Fluoromisonidazole ((18)FMISO) both in vitro, using Walker 256 rat carcinosarcoma cells, and in vivo in experimental rat tumors eleven to twelve days after tumor cell implantation. In vitro studies indicated that hypoxia-selective uptake of both (18)FAZA and (18)FMISO in tumor cells, 20 and 100 minutes post-incubation was of the same magnitude (20 min: 1.24 +/- 0.4% ((18)FAZA); 1.19 +/- 0.7% ((18)FMISO); 100 min: 3.6 +/- 1.6% ((18)FAZA); 3.3 +/- 1.7% ((18)FMISO)). PET imaging reflected a similar radiotracer distribution in rat tumors for (18)FAZA and (18)FMISO one h after radiotracer injection. The concentration of (18)FAZA in the tumors as measured by PET, however, was lower in comparison to (18)FMISO (SUV(FAZA) = 0.61 +/- 0.2 vs. SUV(FMISO) = 0.92 +/- 0.3, p < 0.05) although the tumor to muscle ratios for (18)FAZA and (18)FMISO did not differ in the PET images that were obtained after one h (SUV(FAZA) = 2.5 +/- 0.5 vs. SUV(FMISO) = 2.9 +/- 0.7). A comparison of PET data three h post-injection (SUV(FAZA) = 3.0 +/- 0.5 vs. SUV(FMISO) = 4.6 +/- 1.8, p < 0.05) demonstrated a lower (18)FAZA uptake that indicates a lower sensitivity of (18)FAZA in comparison to (18)FMISO in detecting hypoxic regions at a longer time in this animal model. However, these data also show a faster elimination of (18)FAZA from blood, viscera and muscle tissue, via the renal system. This advantage of a faster reduction of unspecific binding, in light of similar or marginally lower tumor uptake, warrants further investigation of (18)FAZA as a marker of regional hypoxia in tumors.
Nuclear Medicine and Biology 04/2003; 30(3):317-26. · 3.02 Impact Factor
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ABSTRACT: A new sugar-coupled 2-nitroimidazole derivative ([18F](see structure in text)) has been prepared in good radiochemical yields starting from peracetylated 2-[18F]FDG obtained from an automated 2-[18F]FDG production module. The corresponding glucose derivative (see structure in text) has proved to be able to inhibit 2-[18F]FDG uptake into tumor cells in a concentration dependent way. However, [18F](see structure in text) failed to show a retention in hypoxic tumor tissue thus excluding itself from further investigations.
Applied Radiation and Isotopes 12/2002; 57(5):705-12. · 1.17 Impact Factor
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ABSTRACT: Wilson's disease (WD) is a copper deposition disorder which can result in a number of extrapyramidal motoric symptoms such as parkinsonism. Therefore, this study was carried out to investigate, for the first time, nigrostriatal dopaminergic function in WD in relation to different courses and severity of the disease. Using high-resolution single-photon emission tomography (SPET) after administration of 2-carbomethoxy-3-(4[123I]iodophenyl)tropane ([123I]-CIT), striatal dopamine transporters (DAT) were imaged in 43 WD patients and a control group of ten subjects. From the SPET images, specific [123I]-CIT binding ratios were obtained for the caudate heads, putamina and entire corpus striatum. In addition, to evaluate a putative dissociation between the caudate and putaminal [123I]-CIT binding ratios, the ratio between these binding ratios was calculated (CA/PU ratio). The SPET data were compared with clinical data on the course of the disease (CD), the severity of neurological symptoms and the degree of hepatic alteration. Whereas the specific regional [123I]-CIT binding ratios in patients with asymptomatic/hepatic CD did not differ from those in the control group (e.g. striatal ratios: 13.4Dž.0 vs 11.7DŽ.8), in patients with neurological CD the ratios were significantly reduced for all striatal substructures (P=0.003 after one-factor ANOVA). For the different subgroups a tendency was detected towards a stepwise decrease in the specific [123I]-CIT binding ratios from pseudo-sclerosis CD (9.4DŽ.3), through pseudo-parkinsonian CD (9.1DŽ.1) to arrhythmic-hyperkinetic CD (8.5ǃ.6). However, these group differences reached significance only for the comparison with asymptomatic/hepatic CD (P=0.02). The CA/PU ratio was significantly higher in WD than in the control group (1.30ǂ.19 vs 1.11ǂ.08; P=0.003). Severity of neurological symptoms was significantly correlated with all specific regional [123I]-CIT binding ratios (r=-0.49 to -0.57). For degree of liver alteration, significant correlations were obtained with the putaminal binding ratio (r=-0.37) and the CA/PU ratio (r=0.44). From these results is concluded that in WD the nigrostriatal dopaminergic function is compromised to varying extents. The degree of this presynaptic alteration of dopaminergic neurotransmission depends on the clinical course and severity of this copper deposition brain disorder and also varies in the different striatal substructures.
European journal of nuclear medicine and molecular imaging 01/2001; 28(11):1656-1663. · 4.99 Impact Factor
