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Heiko Ihmels - One of the best experts on this subject based on the ideXlab platform.
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Diphenylaminostyryl-substituted Quinolizinium derivatives as fluorescent light-up probes for duplex and quadruplex DNA
Photochemical & Photobiological Sciences, 2019Co-Authors: Avijit Kumar Das, Heiko Ihmels, Sarah KolschAbstract:( E )-2-[1'-((Diphenylamino)styryl)Quinolizinium ( 3a ) and 2,2'-{(phenylimino)-bis[( E )-1″,1″′-styryl]}-bis[quin-olizinium] ( 3b ) were synthesized, and their interactions with duplex DNA and quadruplex DNA were investigated with a particular focus on their ability to operate as DNA-sensitive fluorescent probes. Due to the significantly different size and steric demand of these Quinolizinium derivatives they exhibit different binding modes. Thus, 3a intercalates into duplex DNA and binds through n stacking to quadruplex DNA, whereas 3b favours groove binding to both DNA forms. The emission intensity of these compounds is very low in aqueous solution, but it increases drastically upon association with duplex DNA by a factor of 11 ( 3a ) and >100 ( 3b ) and with quadruplex DNA by a factor of >100 ( 3a ) and 10 ( 3b ), with emission bands between 600 and 750 nm.
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Mild Synthesis of Fluorosolvatochromic and Acidochromic 3‑Hydroxy-4-pyridylisoquinoline Derivatives from Easily Available Substrates
2019Co-Authors: Gabriel E. Gomez Pinheiro, Heiko Ihmels, Christoph DohmenAbstract:The reaction of sodium cyanate with benzo[b]Quinolizinium substrates at room temperature gave 3-hydroxy-4-pyridyl-isoquinoline derivatives in good yields. Presumably, the overall reaction proceeds through an ANRORC-type sequence, that is, addition of the nucleophile, ring opening, and ring closure. Preliminary photophysical investigation of the parent compound revealed a pronounced sensitivity of its emission properties toward solvent effects and the pH of the medium
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Synthesis of 9-arylalkynyl- and 9-aryl-substituted benzo[b]Quinolizinium derivatives by Palladium-mediated cross-coupling reactions
Beilstein-Institut, 2018Co-Authors: Siva Sankar Murthy Bandaru, Darinka Dzubiel, Heiko Ihmels, Mohebodin Karbasiyoun, Mohamed M. A. Mahmoud, Carola SchulzkeAbstract:9-Arylbenzo[b]Quinolizinium derivatives were prepared with base-free Suzuki–Miyaura coupling reactions between benzo[b]Quinolizinium-9-trifluoroborate and selected benzenediazonium salts. In addition, the Sonogashira coupling reaction between 9-iodobenzo[b]Quinolizinium and the arylalkyne derivatives yielded four novel 9-(arylethynyl)benzo[b]Quinolizinium derivatives under relatively mild reaction conditions. The 9-(N,N-dimethylaminophenylethynyl)benzo[b]Quinolizinium is only very weakly emitting, but the emission intensity increases by a factor >200 upon protonation, so that this derivative may operate as pH-sensitive light-up probe. Photometric and fluorimetric titrations of duplex and quadruplex DNA to 9-(arylethynyl)benzo[b]Quinolizinium derivatives revealed a significant binding affinity of these compounds towards both DNA forms with binding constants of Kb = 0.2–2.2 × 105 M−1
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Ratiometric Detection of Water in Acetonitrile with 9-Hydroxybenzo[b]Quinolizinium as Fluorosolvatochromic Probe
Journal of Fluorescence, 2017Co-Authors: Katy Schafer, Heiko IhmelsAbstract:The solvatochromic 9-hydroxybenzo[ b ]Quinolizinium ion is shown to operate as fluorescent probe for the detection of water in acetonitrile. The dual fluorescence of this photoacid and its dependence on the content of water in the medium enable the ratiometric analysis of the fluorescence data. Graphical Abstract ᅟ
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interactions between photoacidic 3 hydroxynaphtho 1 2 b Quinolizinium and cucurbit 7 uril influence on acidity in the ground and excited state
Beilstein Journal of Organic Chemistry, 2017Co-Authors: Jonas Becher, Daria V Berdnikova, Darinka Dzubiel, Heiko Ihmels, Phil M PithanAbstract:3-Hydroxynaphtho[1,2-b]Quinolizinium was synthesized by cyclodehydration route and its optical properties in different media were investigated. The absorption and emission spectra of this compound depend on the pH of the solution. Thus, at higher pH values the deprotonation yields a merocyanine-type dye that exhibits significantly red-shifted absorption bands and causes a dual emisson, i.e., a combination of emission bands of the hydroxyQuinolizinium and its deprotonated form. Whereas this compound is a weak acid in the ground state (pKa = 7.9), it has a strongly increased acidity in the excited state (pKa* = 0.4). As a result, the blue-shifted fluorescence of the hydroxyQuinolizinium becomes dominant only under strongly acidic conditions. In addition, it is shown that 3-hydroxynaphtho[1,2-b]Quinolizinium binds to cucurbit[7]uril (CB[7]) with moderate affinity (Kb = 1.8 × 104 M-1, pH 5) and that the pKa and pKa* values of this ligand increase by about two to three orders of magnitude, respectively, when bound to CB[7].
Juan J. Vaquero - One of the best experts on this subject based on the ideXlab platform.
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Quinolizinium as a new fluorescent lysosomotropic probe
Bioorganic & Medicinal Chemistry Letters, 2017Co-Authors: Emmanouil Zacharioudakis, Ana M. Cuadro, Juan J. Vaquero, Tatiana Caneque, Raul Custodio, Sebastian Muller, Raphael RodriguezAbstract:We have synthesized a collection of Quinolizinium fluorescent dyes for the purpose of cell imaging. Preliminary biological studies in human U2OS osteosarcoma cancer cells have shown that different functional groups appended to the cationic Quinolizinium scaffold efficiently modulate photophysical properties but also cellular distribution. While Quinolizinium probes are known nuclear staining reagents, we have identified a particular Quinolizinium derivative salt that targets the lysosomal compartment. This finding raises the question of predictability of specific organelle targeting from structural features of small molecules.
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nonlinear emission of Quinolizinium based dyes with application in fluorescence lifetime imaging
Journal of Physical Chemistry A, 2015Co-Authors: Gema Marcelo, Ana M. Cuadro, Juan J. Vaquero, Tatiana Caneque, Sandra N Pinto, Ines F A Mariz, J M G Martinho, Ermelinda M S MacoasAbstract:Charged molecules based on the quinolizinum cation have potential applications as labels in fluorescence imaging in biological media under nonlinear excitation. A systematic study of the linear and nonlinear photophysics of derivatives of the quinolizinum cation substituted by either dimethylaniline or methoxyphenyl electron donors is performed. The effects of donor strength, conjugation length, and symmetry in the two-photon emission efficiency are analyzed in detail. The best performing nonlinear fluorophore, with two-photon absorption cross sections of 1140 GM and an emission quantum yield of 0.22, is characterized by a symmetric D-π-A+-π-D architecture based on the methoxyphenyl substituent. Application of this molecule as a fluorescent marker in optical microscopy of living cells revealed that, under favorable conditions, the fluorophore can be localized in the cytoplasmatic compartment of the cell, staining vesicular shape organelles. At higher dye concentrations and longer staining times, the fluor...
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novel charged nlo chromophores based on Quinolizinium acceptor units
Dyes and Pigments, 2014Co-Authors: Tatiana Caneque, Ana M. Cuadro, Julio Alvarezbuilla, Javier Perezmoreno, Koen Clays, Obis Castano, Jose L Andres, Juan J. VaqueroAbstract:Abstract An azonia cation has been explored for the first time as an acceptor unit in charged π-donor π-acceptor chromophores. Initial experimental and theoretical data show that Quinolizinium, the simplest heteroaromatic azonia cation, behaved as a good acceptor unit and conferred promising nonlinear optical properties to simple push–pull cationic chromophores.
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Efficient Synthesis of an IndoloQuinolizinium Alkaloid Selective DNA-Binder by Ring-Closing Metathesis
2014Co-Authors: Beatriz Abarca, Ana M. Cuadro, Julio Alvarez-builla, Raul Custodio, David Sucunza, Alberto Domingo, Francisco Mendicuti, Juan J. VaqueroAbstract:Two total syntheses of the indolo[2,3-a]Quinolizinium cation have been accomplished through the application of two ring-closing metathesis reactions to form the pyridinium ring. One of these approaches provides the tetracyclic cation in only five steps from commercially available harmane. Fluorescence-based thermal denaturation experiments, as well as spectrofluorimetric titration, circular dichroism measurements, and theoretical simulations, showed a consistent DNA-binding capacity by intercalation with a marked preference for AT-rich sequences
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ring closing metathesis approach to heteroaromatic cations synthesis of benzo a Quinolizinium salts
ChemInform, 2011Co-Authors: Ana Nunez, Ana M. Cuadro, Beatriz Abarca, Julio Alvarezbuilla, Juan J. VaqueroAbstract:Benzo[a]Quinolizinium systems such as (II) are prepared by three different approaches, each based on a ring-closing metathesis reaction.
Giampietro Viola - One of the best experts on this subject based on the ideXlab platform.
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control of the dna binding and antiproliferative properties of hydroxybenzo b Quinolizinium derivatives with ph and light
Chemistry: A European Journal, 2017Co-Authors: Katy Schafer, Heiko Ihmels, Elena Porcu, Giampietro ViolaAbstract:The interactions of 8-hydroxybenzo[b]Quinolizinium and 9-hydroxy-benzo[b]Quinolizinium with DNA are investigated in detail. Specifically, spectro¬photometric and spectrofluorimetric titrations, thermal DNA-de¬na¬turation experiments as well as CD- and LD-spectroscopic ana¬lysis show that a pH shift by just one or two orders of magnitude has a significant impact on the interactions of the acidic ligands with the nucleic acid. Both ligands bind with high affinity to DNA at pH = 6 (Kb ≈ 105 M-1). At pH = 7 or 8, however, the binding interactions are much weaker because of the formation of the corresponding charge neutral conjugate bases whose affinity to DNA is reduced due to the resulting lack of a positive charge. Notably, the variation of DNA affinity occurs in a range that corresponds to the fluctuations of pH values under physiological conditions, so that these ligands may be employed to target DNA in tissue with particular pH values, i.e. cancer cells. The antiproliferative activity of the title compounds under different conditions is also investigated. In the absence of irradiation both compounds show only a modest cytotoxicity toward cancer cells. But upon irradiation, even at low UV-A doses, a signifi¬cant reduction of cell viability of tumor cell lines is induced by the ligands.
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synthesis and fluorosolvatochromism of 3 arylnaphtho 1 2 b Quinolizinium derivatives
ChemInform, 2016Co-Authors: Phil M Pithan, Giampietro Viola, David Decker, Manlio Sutero Sardo, Heiko IhmelsAbstract:Cationic biaryl derivatives were synthesized by Suzuki–Miyaura coupling of 3-bromonaphtho[1,2-b]Quinolizinium bromide with arylboronic acids. The resulting cationic biaryl derivatives exhibit pronounced fluorosolvatochromic properties. First photophysical studies in different solvents showed that the emission energy of the biaryl derivatives decreases with increasing solvent polarity. This red-shifted emission in polar solvents is explained by a charge shift (CS) in the excited state and subsequent solvent relaxation. Furthermore, the polarity of protic polar and aprotic polar solvents affects the emission energy to different extent, which indicates a major influence of hydrogen bonding on the stabilization of the ground and excited states.
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benzo b Quinolizinium derivatives have a strong antimalarial activity and inhibit indoleamine dioxygenase
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Esther Jortzik, Heiko Ihmels, Giampietro Viola, Kathleen Zocher, Antje Isernhagen, Boniface M Mailu, Stefan Rahlfs, Sergio Wittlin, Nicholas H Hunt, Katja BeckerAbstract:The heme-containing enzymes indoleamine 2,3-dioxygenase-1 (IDO-1) and IDO-2 catalyze the conversion of the essential amino acid tryptophan into kynurenine. Metabolites of the kynurenine pathway and IDO itself are involved in immunity and the pathology of several diseases, having either immunoregulatory or antimicrobial effects. IDO-1 plays a central role in the pathogenesis of cerebral malaria, which is the most severe and often fatal neurological complication of infection with Plasmodium falciparum. Mouse models are usually used to study the underlying pathophysiology. In this study, we screened a natural compound library against mouse IDO-1 and identified 8-aminobenzo[b]Quinolizinium (compound 2c) to be an inhibitor of IDO-1 with potency at nanomolar concentrations (50% inhibitory concentration, 164 nM). Twenty-one structurally modified derivatives of compound 2c were synthesized for structure-activity relationship analyses. The compounds were found to be selective for IDO-1 over IDO-2. We therefore compared the roles of prominent amino acids in the catalytic mechanisms of the two isoenzymes via homology modeling, site-directed mutagenesis, and kinetic analyses. Notably, methionine 385 of IDO-2 was identified to interfere with the entrance of l-tryptophan to the active site of the enzyme, which explains the selectivity of the inhibitors. Most interestingly, several benzo[b]Quinolizinium derivatives (6 compounds with 50% effective concentration values between 2.1 and 6.7 nM) were found to be highly effective against P. falciparum 3D7 blood stages in cell culture with a mechanism independent of IDO-1 inhibition. We believe that the class of compounds presented here has unique characteristics; it combines the inhibition of mammalian IDO-1 with strong antiparasitic activity, two features that offer potential for drug development.
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selective ratiometric detection of h2o2 in water and in living cells with boronobenzo b Quinolizinium derivatives
Chemical Communications, 2014Co-Authors: Roberta Bortolozzi, Heiko Ihmels, Katy Schafer, Sebastian Von Gradowski, Giampietro ViolaAbstract:Boronobenzo[b]Quinolizinium derivatives exhibit several favorable properties for the fluorimetric detection of hydrogen peroxide, namely quantitative transformation to a product whose emission maximum is well separated from the one of the substrate, water solubility, and the ability to operate in living cells.
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9 4 dimethylaminophenyl benzo b Quinolizinium a near infrared fluorophore for the multicolor analysis of proteins and nucleic acids in living cells
Chemistry: A European Journal, 2013Co-Authors: Roberta Bortolozzi, Heiko Ihmels, Laura Thomas, Maoqun Tian, Giampietro ViolaAbstract:The visualization of cell components or processes within cells is an essential task in bioanalytical chemistry. Specifically, the fluorimetric detection of biomacromolecules has developed as a key technique in this research area, mainly because emission spectroscopy is a highly sensitive and straightforward method with relatively few demands on the equipment. As a consequence, several fluorescent probes have been established that enable the selective detection of cells or cellular components. For example, DNA–fluorophore conjugates, peptide-based molecular beacons, groove-binding cyanine dyes, and light-cleavable caged dyes were shown to operate as DNA stains in live cells. Similarly, it was demonstrated that appropriately substituted metallointercalators have a high propensity to bind to cellular DNA and thus enable its fluorimetric detection, or, in some cases, the detection of other cell components. 11] The same principle was applied to detect RNA in nucleoli and the cytoplasm with a 2,7-carbazole derivative. Furthermore, exciton-controlled hybridization-sensitive fluorescent oligonucleotide (ECHO) probes allow multicolor RNA imaging in cells. Recently, a chemosensor has been presented that enables the fluorimetric differentiation of quadruplex DNA from other nucleic acids in cells. Moreover, it has been shown that the fluorimetric discrimination of regions with different polarities may be accomplished in cells with quinoxaline derivatives. Along these lines, the use of near-infrared (NIR, 650–900 nm) fluorescent probes is advantageous for biological applications, because NIR fluorophores exhibit low or almost no phototoxicity, relatively deep penetration into tissue, and negligible interference with the autofluorescence of cells. We have shown recently that benzo[b]Quinolizinium derivatives may be functionalized such that the fluorescence is quenched by different independent deactivation pathways and that the association with biomacromolecules results in light-up effects and shifts in the emission energy. In some cases, separate deactivation channels enable the indepenACHTUNGTRENNUNGdent or even simultaneous detection of DNA and metal ions with one chemosensor. In this context, we synthesized 9-(4-dimethylamino)benzo[b]Quinolizinium (1a), which exhibits a very low emission quantum yield, presumably caused by deactivation of the excited state by torsional relaxation and photoinduced electron transfer (PET) or charge shift (CS). Notably, some structural features of the derivative 1a resemble aminophenylpyridinium derivatives such as 2, which have been used as fluorescent probes in nerve membranes, and Thioflavin T (3), which has been applied for fluorimetric analysis of amyloid fibril formation. Therefore, we proposed that the derivative 1a may represent a complementary fluorimetric tool for the selective analysis of biomacromolecules, especially considering our experience with the benzo[b]Quinolizinium ion as a ligand for DNA and proteins. Herein, we demonstrate that different physiologically relevant host systems are stained with the chemosensor 1a, most remarkably with different emission wavelengths and intensities. In addition, we show that, due to these properties, the chemosensor 1a represents one of the rare examples of probes that stain cells with multicolored fluorescence.
Ana M. Cuadro - One of the best experts on this subject based on the ideXlab platform.
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Quinolizinium as a new fluorescent lysosomotropic probe
Bioorganic & Medicinal Chemistry Letters, 2017Co-Authors: Emmanouil Zacharioudakis, Ana M. Cuadro, Juan J. Vaquero, Tatiana Caneque, Raul Custodio, Sebastian Muller, Raphael RodriguezAbstract:We have synthesized a collection of Quinolizinium fluorescent dyes for the purpose of cell imaging. Preliminary biological studies in human U2OS osteosarcoma cancer cells have shown that different functional groups appended to the cationic Quinolizinium scaffold efficiently modulate photophysical properties but also cellular distribution. While Quinolizinium probes are known nuclear staining reagents, we have identified a particular Quinolizinium derivative salt that targets the lysosomal compartment. This finding raises the question of predictability of specific organelle targeting from structural features of small molecules.
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nonlinear emission of Quinolizinium based dyes with application in fluorescence lifetime imaging
Journal of Physical Chemistry A, 2015Co-Authors: Gema Marcelo, Ana M. Cuadro, Juan J. Vaquero, Tatiana Caneque, Sandra N Pinto, Ines F A Mariz, J M G Martinho, Ermelinda M S MacoasAbstract:Charged molecules based on the quinolizinum cation have potential applications as labels in fluorescence imaging in biological media under nonlinear excitation. A systematic study of the linear and nonlinear photophysics of derivatives of the quinolizinum cation substituted by either dimethylaniline or methoxyphenyl electron donors is performed. The effects of donor strength, conjugation length, and symmetry in the two-photon emission efficiency are analyzed in detail. The best performing nonlinear fluorophore, with two-photon absorption cross sections of 1140 GM and an emission quantum yield of 0.22, is characterized by a symmetric D-π-A+-π-D architecture based on the methoxyphenyl substituent. Application of this molecule as a fluorescent marker in optical microscopy of living cells revealed that, under favorable conditions, the fluorophore can be localized in the cytoplasmatic compartment of the cell, staining vesicular shape organelles. At higher dye concentrations and longer staining times, the fluor...
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novel charged nlo chromophores based on Quinolizinium acceptor units
Dyes and Pigments, 2014Co-Authors: Tatiana Caneque, Ana M. Cuadro, Julio Alvarezbuilla, Javier Perezmoreno, Koen Clays, Obis Castano, Jose L Andres, Juan J. VaqueroAbstract:Abstract An azonia cation has been explored for the first time as an acceptor unit in charged π-donor π-acceptor chromophores. Initial experimental and theoretical data show that Quinolizinium, the simplest heteroaromatic azonia cation, behaved as a good acceptor unit and conferred promising nonlinear optical properties to simple push–pull cationic chromophores.
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Efficient Synthesis of an IndoloQuinolizinium Alkaloid Selective DNA-Binder by Ring-Closing Metathesis
2014Co-Authors: Beatriz Abarca, Ana M. Cuadro, Julio Alvarez-builla, Raul Custodio, David Sucunza, Alberto Domingo, Francisco Mendicuti, Juan J. VaqueroAbstract:Two total syntheses of the indolo[2,3-a]Quinolizinium cation have been accomplished through the application of two ring-closing metathesis reactions to form the pyridinium ring. One of these approaches provides the tetracyclic cation in only five steps from commercially available harmane. Fluorescence-based thermal denaturation experiments, as well as spectrofluorimetric titration, circular dichroism measurements, and theoretical simulations, showed a consistent DNA-binding capacity by intercalation with a marked preference for AT-rich sequences
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ring closing metathesis approach to heteroaromatic cations synthesis of benzo a Quinolizinium salts
ChemInform, 2011Co-Authors: Ana Nunez, Ana M. Cuadro, Beatriz Abarca, Julio Alvarezbuilla, Juan J. VaqueroAbstract:Benzo[a]Quinolizinium systems such as (II) are prepared by three different approaches, each based on a ring-closing metathesis reaction.
Minoru Maeda - One of the best experts on this subject based on the ideXlab platform.
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4 5 9 10 tetrahydro 1 4 ethanobenz b quinolizine as a prodrug for its Quinolizinium cation as a ligand to the open state of the tcp binding site of nmda receptors
Bioorganic & Medicinal Chemistry Letters, 2001Co-Authors: Shigeki Sasaki, Takahiro Kanda, Nobuyasu Ishibashi, Fumihiko Yamamoto, Terushi Haradahira, Takashi Okauchi, Jun Meda, Kazutoshi Suzuki, Minoru MaedaAbstract:Abstract A new derivative of 4,5,9,10-tetrahydro-1,4-ethanobenz[ b ]quinolizine ( 2 ) has been designed as a prodrug for its Quinolizinium cation ( 1 ) that is a potent antagonist of the TCP-binding site of NMDA receptors at the open state. The 11 C-labeled 2 showed high accumulation of radioactivity in the brain in an in vivo biodistribution study. The speculation of 2 as a prodrug of 1 has been proven by the fact that 1 was observed in a high ratio to 2 in an analysis by RP-HPLC of the brain homogenates.
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synthesis and evaluation of 18f and 11c labelled 9 10 ethanobenzo b Quinolizinium derivatives for imaging of the nmda receptor at the tcp binding site
Journal of Labelled Compounds and Radiopharmaceuticals, 2000Co-Authors: Nobuyasu Ishibashi, Shigeki Sasaki, Fumihiko Yamamoto, Terushi Haradahira, Kazutoshi Suzuki, Tsuneo Kuwamura, Hiromi Sano, Tetsuya Suhara, Minoru MaedaAbstract:Derivatives of 9,10-ethanobenzo[b]Quinolizinium are potent antagonists for the TCP-site of the NMDA receptor. Two fluoroethyl-substituted analogues were labelled with fluorine-18 by displacement of the tosylate with [18F]fluoride, followed by a Diels-Alder reaction. A methoxy-substituted analogue labelled with carbon-11 was obtained by O-methylation of the corresponding hydroxy precursor with [11C]iodomethane. In biodistribution studies in mice with these three radioligands, it was found that they have little ability to penetrate the blood-–brain barrier. Copyright © 2000 John Wiley & Sons, Ltd.
