Publications by authors named "Marion Kretzschmar"

7 Publications

  • Page 1 of 1

[11C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats.

Nucl Med Biol 2006 Jan;33(1):53-63

Institut für Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, Dresden, Germany.

N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (SMe-ADAM, 1) is a highly potent and selective inhibitor of the serotonin transporter (SERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [(11)C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [(11)C]SMe-ADAM. The radiochemical yield was 27 +/- 5%, and the specific radioactivity was 26-40 GBq/micromol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SERT, such as the thalamus/hypothalamus region (3.59 +/- 0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74 +/- 0.95 at 60 min postinjection. The [(11)C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38 +/- 11% of the control value. Furthermore, no metabolites of [(11)C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [(11)C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain.
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http://dx.doi.org/10.1016/j.nucmedbio.2005.07.009DOI Listing
January 2006

Synthesis and radiopharmacological evaluation of 2'-(4-fluorophenyl)-21-[18F]fluoro-20-oxo-11beta,17alpha-dihydroxy-pregn-4-eno[3,2-c]pyrazole as potential glucocorticoid receptor ligand for positron emission tomography (PET).

Bioorg Med Chem Lett 2005 Mar;15(5):1303-6

Institut für Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf e.V., PO Box 51 01 19, D-01314 Dresden, Germany.

The radiosynthesis and the radiopharmacological evaluation of pyrazolo steroid 2'-(4-fluorophenyl)-21-[18F]fluoro-20-oxo-11beta,17alpha-dihydroxy-pregn-4-eno[3,2-c]pyrazole [18F]-2 is described. The radiolabeling was accomplished in 3-4% decay-corrected radiochemical yield within 80 min at an specific radioactivity of 0.8-1.2 Ci/micromol. Biodistribution studies in male Wistar rats showed an initial brain uptake of 0.25+/-0.03% ID/g after 5 min, which remained constant over 60 min. The radiopharmacological evaluation of compound [18F]-2 was completed with autoradiography using rat brain sections and micro-PET imaging.
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http://dx.doi.org/10.1016/j.bmcl.2005.01.033DOI Listing
March 2005

Autoradiographic imaging of the serotonin transporter in the brain of rats and pigs using S-([18F]fluoromethyl)-(+)-McN5652.

Eur Neuropsychopharmacol 2003 Oct;13(5):387-97

Institut für Bioanorganische und Radiopharmazeutische Chemie, PF 510119, 01314 Dresden, Germany.

The [18F]fluoromethyl analogue of (+)-McN5652 ([18F]FMe-McN) has recently been developed as a radioligand for imaging the neuronal serotonin transporter (SERT) with positron emission tomography (PET). We describe here the autoradiographic evaluation of [18F]FMe-McN in the brain of rats and pigs. Autoradiographic studies of [18F]FMe-McN performed on rat and pig brain in vitro showed a high accumulation of radioactivity in the regions rich in SERT, such as amygdala, hypothalamus, superficial gray layer of the superior colliculus, various nuclei of thalamus and substantia nigra. The binding of [18F]FMe-McN was reduced by citalopram, a highly selective inhibitor for SERT. Similar regional specific binding densities of [18F]FMe-McN were observed in both species. The regional distribution and specific binding of this radiotracer correlates well with the distribution and regional brain binding of [3H]citalopram. Region-to-cerebellum ratios of [18F]FMe-McN in vitro reached a maximum value of 20.6 in the rat and 14.5 in the pig. In addition, ex vivo autoradiography of the rat brain was performed 90 min after i.v. administration of [18F]FMe-McN. The highest regional uptake of [18F]FMe-McN was observed in the hypothalamic area, substantia nigra and amygdaloid area. There is a high correlation between the in vitro and in vivo binding. The region-to-cerebellum ratio in vivo reached a maximum value of 5.1 in the substantia nigra, the highest yet reported for an 18F-labelled SERT tracer in vivo in this region. Furthermore, the distribution volume of [18F]FMe-McN calculated from the PET data in various regions of the porcine brain is highly correlated with the SERT density as determined by in vitro autoradiography with [3H]citalopram. Thus, [18F]FMe-McN has a clear potential as a radiotracer for studies of the SERT distribution in man with PET.
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http://dx.doi.org/10.1016/s0924-977x(03)00039-7DOI Listing
October 2003

Autoradiographic analyses of 5-HT1A and 5-HT2A receptors after social isolation in mice.

Brain Res 2003 Aug;980(2):169-78

AG Neurobiologie, Klinik für Psychiatrie, TU, Dresden, Germany.

Social isolation of rodents is used to model human psychopathological processes. In the present study, the effects of intermediate and long term isolation housing on postsynaptic 5-HT(1A) and 5-HT(2A) receptors were analyzed in male mice housed in groups or isolation for 4 and 12 weeks. [3H]8-OH-DPAT and [3H]ketanserin were used to label 5-HT(1A) and 5-HT(2A) receptors. Four representative sagittal sections (planes 1-4) were scored by in vitro autoradiography. Whereas after 4 weeks of housing both receptor densities were lowered significantly in isolated mice, after 12 weeks of housing only marginal isolation effects were seen. Intermediate isolation reduced 5-HT(1A) receptors especially in the lateral frontal, parietal and entorhinal cortex (-63%), in the lateral CA1-3 and dentate gyrus region of the hippocampus (-68%), in the basolateral, basomedial, central and medial amygdaloid nuclei (between -38 and -66%), and in the hypothalamus (-28%). 5-HT(2A) receptors were strongly reduced in the frontal cortex (between -47 and -74%), in the hippocampus (between -47 and -95%), in the striatum (between -66 and -76%), and in the accumbens nucleus (between -59 and -73%) in comparison to group housed control mice. After 12 weeks of isolation in the hippocampus continuously decreased 5-HT(1A) receptor densities were demonstrated (between -24 and -61%). But increased 5-HT(2A) receptor densities were seen in the lateral striatum (+86%) compared to control mice. Age-dependent effects were also found. After 12 weeks of group housing the 5-HT(1A) and 5-HT(2A) receptor densities were decreased (between -28 and -54%) in all analyzed brain regions in comparison to 4 weeks of group housing. Isolated animals showed diminished 5-HT(1A) receptor densities in the cortex (-14%) and hippocampus (-15%), but increased 5-HT(1A) receptor densities in the amygdala (+33%) after 12 weeks. The 5-HT(2A) receptor densities were increased in all analyzed regions (between +31 and +96%) after 12 weeks of isolation compared to 4 weeks. To explain these dynamic, time-dependent pattern of isolation-induced changes different regulation processes are supposed regarding 5-HT(1A) and 5-HT(2A) receptors. Besides metabolism-related adaptation processes also neurotransmitter and hormonal (e.g., glucocorticoid) interactions especially in limbic regions have to be considered.
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http://dx.doi.org/10.1016/s0006-8993(03)02832-4DOI Listing
August 2003

Positron emission tomography imaging of the serotonin transporter in the pig brain using [11C](+)-McN5652 and S-([18F]fluoromethyl)-(+)-McN5652.

Synapse 2003 Feb;47(2):143-51

Institut für Interdisziplinäre Isotopenforschung, 04318 Leipzig, Germany.

S-([(18)F]fluoromethyl)-(+)-McN5652 ([(18)F](+)-FMe-McN5652) has recently been synthesized as a new potential radiotracer for positron emission tomography (PET) imaging of the 5-HT transporter. It is an analog of [(11)C](+)McN5652, which has been used in clinical PET studies for 5-HT transporter imaging. This article describes the comparison of these two radiotracers in pigs with respect to their in vivo binding characteristics. PET images revealed that the highest accumulation of both radiotracers was found in the ventral midbrain, thalamus, olfactory lobe, and pons which is consistent with the known density of 5-HT transporters. The specific binding was determined by subtracting the values of the inactive (-) enantiomers or of the occipital cortex from those obtained with [(11)C](+)McN5652 or [(18)F](+)-FMe-McN5652 in the time period between 75 and 115 min after radiotracer injection. The specific binding of the (18)F-labeled derivative was about 40% higher than that of the (11)C-labeled derivative. A strong inhibition of the specific binding was observed for both radiotracers after pretreatment with the selective 5-HT uptake inhibitor citalopram. [(18)F](+)-FMe-McN5652 showed faster kinetics than [(11)C](+)McN5652. It reached the binding equilibrium during a study length of 120 min, which was not the case for [(11)C](+)McN5652. It is concluded that [(18)F](+)-FMe-McN5652 is suitable for 5-HT transporter imaging with PET.
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http://dx.doi.org/10.1002/syn.10163DOI Listing
February 2003

A novel technetium-99m radioligand for the 5-HT(1A) receptor derived from desmethyl-WAY-100635 (DWAY).

Eur J Nucl Med Mol Imaging 2002 Jan 10;29(1):82-7. Epub 2001 Nov 10.

Forschungszentrum Rossendorf, Institut für Bioanorganische und Radiopharmazeutische Chemie, PF 510119, 01314 Dresden, Germany.

This paper reports the synthesis, biological evaluation and in vitro autoradiography of a new technetium-99m radioligand with high affinity for the 5-HT(1A) receptor. The neutral complex combines an N(2)S(2) diamine dithiol (DADT) ligand as complexing moiety for oxotechnetium(V) and a 2-(1-piperazino)phenol via a 6-carbon alkyl chain, derived from desmethyl-WAY 100635 (DWAY). The complex displays an IC(50) value for the 5-HT(1A) receptor of 1.29 n M against the selective 5-HT(1A) agonist [(3)H]8-OH-DPAT, a moderate selectivity towards the alpha(1)-adrenergic receptor (IC(50) of 8.1 n M against [(3)H]prazosin) and a good selectivity for the D(2) receptor (IC(50) of 192 n M against [(3)H]spiperone) and the 5-HT(2A)receptor (IC(50) of 922 n M against [(3)H]ketanserin). Biodistribution studies in rats show an initial brain uptake of 0.56%+/-0.07% ID 2.5 min p.i. In vitro autoradiographic studies of the (99m)Tc complex in rat brains indicate a strong specific accumulation of the radioactivity in 5-HT(1A) receptor-rich brain regions.
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http://dx.doi.org/10.1007/s00259-001-0660-xDOI Listing
January 2002

Biodistribution and catabolism of (18)F-labeled neurotensin(8-13) analogs.

Nucl Med Biol 2002 Jan;29(1):61-72

Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, Germany.

4-([(18)F]fluoro)benzoyl-neurotensin(8-13) ((18)FB-Arg(8)-Arg(9)-Pro(10)-Tyr(11)- Ile(12)-Leu(13)-OH, 1) and two analogs stabilized in one and two positions ((18)FB-Arg(8)psi(CH(2)NH)Arg(9)-Pro(10)-Tyr(11)- Ile(12)-Leu(13)-OH, 2, (18)FB-Arg(8)psi(CH(2)NH)Arg(9)-Pro(10)-Tyr(11)-Tle(12)-Leu(13)-OH, 3) were synthesized in a radiochemical yield of 25-36% and a specific activity of 5-15 GBq/mmol. The peptides were evaluated in vitro and in vivo for their potential to image tumors overexpressing neurotensin receptor 1 (NTR1) by positron emission tomography (PET). All analogs exhibited in vitro binding affinity in the low nanomolar range to NTR1-expressing human tumors, measured by quantitative receptor autoradiography, HT-29 and WiDr cells, and to sections of tumors derived from these cell lines in mice. The radiotracers were internalized in the cells in vitro, and the fluorinated peptides were able to mobilize intracellular Ca(2+) of WiDr cells. In in vivo studies in rats and in mice bearing HT-29 cell tumors, only a moderate uptake of the radioligands into the studied tumors was observed, presumed to be due to degradation in vivo and fast elimination by the kidneys. In comparison with the other analogs, the specific tumor uptake expressed as tumor-to-muscle relation was highest for the radioligand 3. The blood clearance of 3 was reduced by co-injection of peptidase inhibitors. The catabolic pathways of the radiofluorinated peptides were elucidated. The results suggest that the high binding affinity to NTR1 and the stabilization against proteolytic degradation are not yet sufficient for tumor imaging by PET.
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http://dx.doi.org/10.1016/s0969-8051(01)00284-0DOI Listing
January 2002