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Abstract: The specific binding and regional brain pharmacokinetics of new fluorine-18 ([18F])-labeled radioligands for the vesicular monoamine transporter (VMAT2) were examined in the rat and primate brain. In the rat, 9-[18F]fluoropropyl-(±)-9-O-desmethyldihydrotetrabenazine ([18F]FP-(±)-DTBZ) showed better specific binding in the striatum than either (+)-[11C]dihydrotetrabenazine ((+)-[11C]DTBZ) or 9-[18F]fluoroethyl-(±)-9-O-desmethyldihydrotetrabenazine ([18F]FE-(±)-DTBZ). Using microPET, the regional brain pharmacokinetics of [18F]FE-(±)-DTBZ, [18F]FP-(±)-DTBZ and (+)-[11C]DTBZ were examined in the same monkey brain. (+)-[11C]DTBZ and [18F]FP-(±)-DTBZ showed similar brain uptakes and pharmacokinetics, with similar maximum striatum-to-cerebellum ratios (STR/CBL=5.24 and 5.15, respectively) that were significantly better than obtained for [18F]FE-(±)-DTBZ (STR/CBL=2.55). Striatal distribution volume ratios calculated using Logan plot analysis confirmed the better specific binding for the fluoropropyl compound [distribution volume ratio (DVR)=3.32] vs. the fluoroethyl compound (DVR=2.37). Using the resolved single active isomer of the fluoropropyl compound, [18F]FP-(+)-DTBZ, even better specific to nonspecific distribution was obtained, yielding the highest distribution volume ratio (DVR=6.2) yet obtained for a VMAT2 ligand in any species. The binding of [18F]FP-(+)-DTBZ to the VMAT2 was shown to be reversible by administration of a competing dose of unlabeled tetrabenazine. Metabolic defluorination was slow and minor for the [18F]fluoroalkyl-DTBZ ligands. The characteristics of high specific binding ratio, reversibility, metabolic stability and longer half-life of the radionuclide make [18F]FP-(+)-DTBZ a promising alternative VMAT2 radioligand suitable for widespread use in human positron emission tomography studies of monoaminergic innervation of the brain. [Copyright &y& Elsevier]

Bicyclic lactams derived from pyroglutamic acid provide a useful scaffold for synthesis of conformationally restricted analogues of lysine, ornithine and glutamine, as well as an Ala-Ala dipeptide analogue. Amino alcohol and carboxylic acid derivatives are accessible from a common intermediate. In this strategy, the bicyclic lactam system not only controls, but also facilitates the determination of the stereochemistry of the synthetic intermediates.

[reaction: see text] Scalemic acyclic alpha-(alkoxy)alkyl- and alpha-(N-carbamoyl)alkylcuprates prepared from organostannanes via organolithium reagents react with vinyl iodides, propargyl mesylates, and alpha,beta-enones to afford coupled products with enantioselectivities ranging from 0 to 99% ee depending upon cuprate reagent, substrate structure, solvent, and temperature. In general, lithium cuprates give higher chemical yields and lower enantioselectivities, while the trends are reversed for the corresponding zinc cuprate reagents.

Alkylation reactions using alpha-halolactams or lactam enolates derived from bicyclic lactam templates can proceed with high endo- or exo- diastereoselectivity respectively. In the latter case, stereochemical correction by means of enolate generation and hindered phenol quench is possible with moderate efficiency. This protocol has been applied to the synthesis of protected penmacric acid and its analogues.

[reaction: see text]. Metal carbenoid chemistry is used to convert delta-amino beta-ketoesters into 5-substituted 3-oxo prolines, which expands the utility of this class of polyfunctionalized chiral building blocks.