A new and extensive set of 4-(6-iodo-H-imidazo[1,2-a]pyridin-2-yl)-N-dimethylbenzeneamine (IMPY) derivatives was synthesized and assayed for affinity toward human A beta plaques. 6-Ethylthio- (12h), 6-cyano-(12e), 6-nitro- (12f), and 6-p-methoxybenzylthio- (15d) analogues were discovered to have high affinity (K-I < 10 nM). However, introduction of a hydrophilic thioether group in the 6-position (15a-c, 15e-g) reduced or abolished affinity. In secondary N-methyl analogues, a bromo substiment in the adjacent ring position (14a) imparted high affinity (K-1 = 7.4 nM) whereas a methyl substituent did not (14c). The tolerance for nonhydrophilic thioether substituents in the 6-position opens up the possibility of developing new sensitive positron emission tomography radioligands for imaging human A beta plaques in Alzheimer's disease, especially in view of the amenability of thioethers to be labeled with carbon-11 or fluorine-18 through S-alkylation reactions. The structure-activity relationships revealed in this study extends insight into the topography of the binding site for IMPY-like ligands in human A beta plaques.

The addition of radical scavengers to the fluoridation of diaryliodonium salts was demonstrated to improve significantly both the reproducibility of the process and the material yield of the desired fluoroarene products. It was also established that the selectivity of the process was not influenced by the presence of the radical scavengers. TEMPO and galvinoxyl were found to be the most suitable radical scavengers in the fluoridation process allowing the methodology to be used routinely for the first time. (c) 2006 Published by Elsevier B.V.

Meeting Programme Prof David O'Hagan [University of St Andrews, UK]—Enzymatic C–18F Bond Synthesis: A New Strategy for PET Synthesis. Dr Michael Carroll [University of Newcastle, UK]—Studies Towards 6-[18F]Fluoro-m-tyramine using Iodonium Salts. Dr John Gardiner [University of Manchester, UK]—Methods Towards Isotopomer-Versatile Synthesis of 13C-Labelled Carbohydrates. Prof William Lockley [University of Surrey, UK]—Some New Catalytic Systems for Isotope-Exchange Labelling. Dr David Rustidge [Scynexis Europe, UK]—14C-Synthesis—Not Always as Easy as it Looks. Dr Richard Hartley [University of Glasgow, UK]—The Potential for using Titanium Alkylidene Chemistry in Solid-Phase Radiochemical Synthesis. Dr Ian Wilson [Turku Imanet, Finland]—Transition of PET Tracers from Clinical Research Tools to Commercial Diagnostics. Dr Simon Harwood [GlaxoSmithKline, UK]—The Synthesis of Stable Labelled Ketamine. Dr John Herbert [Sanofi-Aventis, UK]—Towards Robust Conditions for Iridium-mediated Exchange. Dr Conor Barry [University of Bristol, UK]—Total Synthesis of Clavosolide A.

This study evaluated F-18-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Abeta-aggregates with K-i = 27 +/- 8 and 40 +/- 5 nM, respectively. A "one-pot" method for F-18-2-fluoroethylation and F-18-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [F-18]FEM-IMPY at 1.2 min, and 5.7% ID/g for [F-18]FPM-IMPY at 0.8 min. These values were similar to those of [I-123/I-123]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [F-18]FEM or [F-18]FPM-IMPY. In contrast to the single-exponential washout of [I-123/I-123]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [F-18] FEM-IMPY and 2.1% ID/g for [F-18]FPM-IMPY. Substantial skull uptake of [F-18]fluoride was also clearly observed. With a view to slow the metabolism of [F-18]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D-4-[F-18]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [F-18]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [F-18]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging beta-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.

This study evaluated (18)F-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Abeta-aggregates with K(i) = 27 +/- 8 and 40 +/- 5 nM, respectively. A "one-pot" method for (18)F-2-fluoroethylation and (18)F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [(18)F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [(18)F]FPM-IMPY at 0.8 min. These values were similar to those of [(123)I/(125)I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [(18)F]FEM or [(18)F]FPM-IMPY. In contrast to the single-exponential washout of [(123)I/(125)I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [(18)F]FEM-IMPY and 2.1% ID/g for [(18)F]FPM-IMPY. Substantial skull uptake of [(18)F]fluoride was also clearly observed. With a view to slow the metabolism of [(18)F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D(4)-[(18)F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [(18)F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [(18)F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging beta-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.

Abstract“Synthesis & Application of Labelled Compounds 2002”Isotopes and Mass SpectrometryCarbon‐13 Labelling to Aid the Development of the Catalytic Alkenation of CarbonylsProduction and Applications of 124I for Positron Emission TomographyOrganic Photochemistry: Synthetic Approaches to Alkaloids in a Reagentless EnvironmentFluorinaion for Positron Emission TomographySynthetic Consequences of Kinetic Isotopes Effects: Synthesis of [13 C6]‐SR31742A For Human Trail PurposesTritio‐Dehalogenation: New Variants on an Old ThemeThe Synthesis of BOC‐L‐Proline‐[14C2] Benzyl EsterPeptide Labelling with Fluorine‐18

An ab initio molecular orbital study using both gas-phase and B3LYP/DZVP-COSMO solvation models of the mechanism of palladium insertion into alkyne and aryl carbon–halogen bonds suggests that the mechanism of palladium insertion into alkyne species can proceed via a concerted oxidative addition across the carbon–halogen bond. A stepwise mechanism via a σ-complex is favoured when a nitro group is introduced onto the alkyne. The palladium insertion into variously substituted aryl fluorides was again found to proceed via a single-step concerted mechanism, and although a σ-complex can be located when 2,4-dinitro and 2-nitro substitution is present, the energy of this stepwise route is very similar to the concerted pathway and no clear decision on the pathway can be made. No intermediate σ-complex could be located for η6-tricarbonylchromium-complexed fluorobenzene, and only a concerted pathway was identified.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

MNDO-d and ab initio RHF, B3LYP and MP2 energies and geometries are reported for reactant ground and transition states for F-R' and R-R' extrusion and R/R' interconversion reactions of substituted RR'I-F iodine(III) reactive intermediates. The RR'I-F reactant is predicted to form a stable asymmetric bridged dimer involving a square planar iodine centre, hitherto unconsidered as a factor in the chemistry of hypervalent iodine species. Evidence in support of this hypothesis obtained from previously reported crystal structures is discussed. The reactions of both monomer and bridged dimer are found to exhibit unusually large stereoelectronic effects at the iodine centre, deriving from electron donating and withdrawing substituents on the R groups. They are also unusual in showing transition state substituent effects which are opposite to those controlling the ground state stabilities, for which an NBO analysis is presented. Both these effects are manifest in the transition states for reaction of the dimeric species, which is stabilised by electron withdrawing groups present in the pseudo equatorial R' group of the reacting centre and in the pseudo axial position of the unreacting R component of the dimer.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The N-methyldiethanolamine esters of arylboronic acids (1-aryl-5-methyl-2,8-dioxa-5-azonia-1-boratabicyclo[3.3.0]-octanes) can be converted to the corresponding fluoroaromatics (6 examples) on treatment with caesium fluoroxysulphate and 1,3-dinitrobenzene in acetonitrile at room temperature.

Phenols, as their trifluoromethanesulphonate (triflate) esters, are converted by potassium cyanide in the presence of catalytic tetrakistriphenylphosphinenickel(0) into the corresponding nitrites, thence to the carboxylic acids.

AbstractDie Hydrierung der Seitenkette von Ergosterin zur Gewinnung der Titelverbindung (IVa) erfordert den vorherigen Schutz des Ring‐B‐Diensystems.

Two efficient routes to bis-(2-arylethyl)amines have been developed by using regiospecific alkylation of dialkylnitrosamine anions and homologation of aromatic aldehydes with methoxyacetonitrile anion as the respective key steps. The hitherto uncharacterised 1,3-diaryl-2-azonia-allene ions have been prepared in isolable form. Attempted insertion of C1 fragments into these systems as a third route to the title compounds failed.