Characterization of optically resolved 9-fluoropropyl-dihydrotetrabenazine as a potential PET imaging agent targeting vesicular monoamine transporters.

Labeling derivatives of dihydrotetrabenazine (DTBZ) with F-18 (T(1/2)=110 min) instead of C-11 (T(1/2)=20 min) would improve their utility and availability for imaging vesicular monoamine transporters (VMAT2) in clinical settings. The successful synthesis, reported previously, of two novel 9-fluoroalkyl(+/-)-DTBZ ligands prompted us to study the optically resolved active ligand 9-fluoropropyl-(+)-DTBZ (FP-(+)-DTBZ), which may have more promising characteristics. The inhibition constant (K(i)) estimated for FP-(+)-DTBZ (using [(3)H](+/-)-DTBZ as the labeled ligand in rat striatal homogenates) showed a lower value as compared to the racemic FP-(+/-)-DTBZ (0.

Pharmacokinetics of [(18)F]fluoroalkyl derivatives of dihydrotetrabenazine in rat and monkey brain.

The specific binding and regional brain pharmacokinetics of new fluorine-18 ([(18)F])-labeled radioligands for the vesicular monoamine transporter (VMAT2) were examined in the rat and primate brain. In the rat, 9-[(18)F]fluoropropyl-(+/-)-9-O-desmethyldihydrotetrabenazine ([(18)F]FP-(+/-)-DTBZ) showed better specific binding in the striatum than either (+)-[(11)C]dihydrotetrabenazine ((+)-[(11)C]DTBZ) or 9-[(18)F]fluoroethyl-(+/-)-9-O-desmethyldihydrotetrabenazine ([(18)F]FE-(+/-)-DTBZ). Using microPET, the regional brain pharmacokinetics of [(18)F]FE-(+/-)-DTBZ, [(18)F]FP-(+/-)-DTBZ and (+)-[(11)C]DTBZ were examined in the same monkey brain.

Fluoroalkyl derivatives of dihydrotetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters.

Imaging of vesicular monoamine transporter 2 (VMAT2) in the brain with [(11)C]-dihydrotetrabenazine (DTBZ) in conjunction with positron emission tomography (PET) has demonstrated its usefulness in the diagnosis and monitoring of neurodegenerative diseases such as Parkinson's disease and Huntington's disease. We report on the development of (18)F analogs of DTBZ with a longer half-life (t=110 vs. 20 min for C-11) to increase the availability of VMAT2 imaging agents for routine clinical studies with PET.

Stereoselective synthesis of conformationally constrained omega-amino acid analogues from pyroglutamic acid.

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.

Enantioselective reactions of scalemic acyclic alpha-(alkoxy)alkyl- and alpha-(N-carbamoyl)alkylcuprates.

[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.

Pyrrolidinones derived from (S)-pyroglutamic acid: penmacric acid and analogues.

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.

Asymmetric synthesis of substituted prolines from delta-amino beta-ketoesters. Methyl (2S,5R)-(+)-5-phenylpyrrolidine-2-carboxylate.

[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.