Co-reporter:Hanno Schieferstein, Markus Piel, Friderike Beyerlein, Hartmut Lüddens, Nicole Bausbacher, Hans-Georg Buchholz, Tobias L. Ross, Frank Rösch
Bioorganic & Medicinal Chemistry 2015 23(3) pp: 612-623
Publication Date(Web):
DOI:10.1016/j.bmc.2014.11.040
Co-reporter:Markus Piel ; Ingo Vernaleken ;Frank Rösch
Journal of Medicinal Chemistry 2014 Volume 57(Issue 22) pp:9232-9258
Publication Date(Web):August 21, 2014
DOI:10.1021/jm5001858
Molecular imaging methods such as positron emission tomography (PET) are increasingly involved in the development of new drugs. Using radioactive tracers as imaging probes, PET allows the determination of the pharmacokinetic and pharmacodynamic properties of a drug candidate, via recording target engagement, the pattern of distribution, and metabolism. Because of the noninvasive nature and quantitative end point obtainable by molecular imaging, it seems inherently suited for the examination of a pharmaceutical’s behavior in the brain. Molecular imaging, most especially PET, can therefore be a valuable tool in CNS drug research. In this Perspective, we present the basic principles of PET, the importance of appropriate tracer selection, the impact of improved radiopharmaceutical chemistry in radiotracer development, and the different roles that PET can fulfill in CNS drug research.
Co-reporter:Friederike Beyerlein;Sabine Höhnemann ;Frank Rösch
Journal of Labelled Compounds and Radiopharmaceuticals 2013 Volume 56( Issue 7) pp:360-363
Publication Date(Web):
DOI:10.1002/jlcr.3043
Abstract
Automated synthetic procedures of [18F]fluoro-[di-deutero]methyl tosylate on a GE TRACERlab FX F-N module and a non-commercial synthesis module have been developed. The syntheses included azeotropic drying of the [18F]fluoride, nucleophilic 18F-fluorination of bis(tosyloxy)-[di-deutero]methane, HPLC purification and subsequent formulation of the synthesized [18F]fluoro-[di-deutero]methyl tosylate (d2-[18F]FMT) in organic solvents. Automation shortened the total synthesis time to 50 min, resulting in an average radiochemical yield of about 50% and high radiochemical purity (>98%). The possible application of this procedure to commercially available synthesis modules might be of significance for the production of deuterated 18F-fluoromethylated imaging probes in the future. Copyright © 2013 John Wiley & Sons, Ltd.
Co-reporter:A. Bauman;M. Piel;S. Höhnemann;A. Krauss;M. Jansen;C. Solbach;G. Dannhardt;F. Rösch
Journal of Labelled Compounds and Radiopharmaceuticals 2011 Volume 54( Issue 10) pp:
Publication Date(Web):
DOI:10.1002/jlcr.1901
The N-methyl- d-aspartate (NMDA) receptor as a type of ionotropic glutamatergic receptors is essential for physiological processes such as learning, memory and synaptic plasticity. A glutamate-induced overactivation of these receptors, accompanied by increased intracellular calcium concentration, causes cell injury and leads to a large number of acute or chronic neurological disorders, such as stroke, trauma, Parkinson's disease and Alzheimer's disease. In an attempt to visualise the glutamatergic neurotransmission in vivo with positron emission tomography, novel fluoroethoxy- and methoxy-substituted reference compounds based on the lead structure of a hydantoin-substituted indole-2-carboxylic acid were synthesised. The affinities towards the glycine binding site of the NMDA receptor showed Ki values between 322 and 11 nM and the lipophilicities ranged from logD values of 1.51 to 2.53. On the basis of these results, precursor compounds were synthesised containing a phenolic hydroxy moiety to obtain the radiolabelled ligands through an alkylation reaction. Radiosynthesis was achieved by labelling the precursor ethyl 4,6-dichloro-3-((3-(4-hydroxyphenyl)-2,4-dioxoimidazolidin-1-yl)methyl)-indole-2-carboxylate with 2-[18F]fluoroethyl tosylate or [11C]methyl iodide and subsequent cleavage of the ethyl ester moiety. This gave the final products in overall decay-corrected radiochemical yields of 5–7% and 6–9% and specific activities of 24–67 GBq/µmol and 8–26 GBq/µmol, respectively.
Co-reporter:Markus Piel, Ulrich Schmitt, Nicole Bausbacher, Hans-Georg Buchholz, Gerhard Gründer, Christoph Hiemke, Frank Rösch
Neuropharmacology (September 2014) Volume 84() pp:152-158
Publication Date(Web):1 September 2014
DOI:10.1016/j.neuropharm.2013.04.062
•A possible influence of P-gp on the brain uptake of [18F]fallypride was examined.•For examination microPET imaging studies in a rat and a mouse model were performed.•Both models indicate that P-gp modulates the brain uptake of [18F]fallypride.•These results may be relevant to further PET studies utilizing [18F]fallypride.[18F]Fallypride ([18F]FP) is an important and routinely used D2/D3 antagonist for quantitative imaging of dopaminergic neurotransmission in vivo. Recently it was shown that the brain uptake of the structurally related [11C]raclopride is modulated by P-glycoprotein (P-gp), an important efflux transporter at the blood–brain barrier. The purpose of this study was to determine whether the brain uptake of [18F]FP is influenced by P-gp. For examination of this possible modulation microPET studies were performed in a rat and a mouse model. Hence, [18F]FP was applied to Sprague Dawley rats, half of them being treated with the P-gp inhibitor cyclosporine A (CsA). In a second experimental series the tracer was applied to three different groups of FVB/N mice: wild type, P-gp double knockout (abcb1a/1b (−/−)) and CsA-treated mice. In CsA-treated Sprague Dawley rats [18F]FP showed an elevated standard uptake value in the striatum compared to the control animals. In FVB/N mice a similar effect was observed, showing an increasing uptake from wild type to CsA-treated and double knockout mice. Since genetically or pharmacologically induced reduction of P-gp activity increased the uptake of [18F]FP markedly, we conclude that [18F]FP is indeed a substrate of P-gp and that the efflux pump modulates its brain uptake. This effect – if true for humans – may have particular impact on clinical studies using [18F]FP for assessment of D2/3 receptor occupancy by antipsychotic drugs.This article is part of the Special Issue Section entitled ‘Neuroimaging in Neuropharmacology’.
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