Synthesis, Radiolabeling, and Biological Evaluation of (R)- and (S)-2-Amino-5-[(18)F]fluoro-2-methylpentanoic Acid ((R)-, (S)-[(18)F]FAMPe) as Potential Positron Emission Tomography Tracers for Brain Tumors.

A novel (18)F-labeled α,α-disubstituted amino acid-based tracer, 2-amino-5-[(18)F]fluoro-2-methylpentanoic acid ([(18)F]FAMPe), has been developed for brain tumor imaging with a longer alkyl side chain than previously reported compounds to increase brain availability via system L amino acid transport. Both enantiomers of [(18)F]FAMPe were obtained in good radiochemical yield (24-52% n = 8) and high radiochemical purity (>99%). In vitro uptake assays in mouse DBT gliomas cells revealed that (S)-[(18)F]FAMPe enters cells partly via sodium-independent system L transporters and also via other nonsystem A transport systems including transporters that recognize glutamine. Biodistribution and small animal PET/CT studies in the mouse DBT model of glioblastoma showed that both (R)- and (S)-[(18)F]FAMPe have good tumor imaging properties with the (S)-enantiomer providing higher tumor uptake and tumor to brain ratios. Comparison of the SUVs showed that (S)-[(18)F]FAMPe had higher tumor to brain ratios compared to (S)-[(18)F]FET, a well-established system L substrate.

Stereoselective synthesis of (2S,3R)-α-hydroxy-ß-amino acids (AHBAs): valinoctin A, (2S,3R)-3-amino-2-hydroxydecanoic acid, and a fluorescent-labeled (2S,3R)-AHBA.

We report the stereoselective synthesis of an alkynyl side-chain containing (2S,3R)-α-hydroxy-ß-amino acid ((2S,3R)-AHBA) analogues. The Cu(I)-catalyzed reactions of (R)-glyceraldehyde acetonide and dibenzylamine with terminal alkynes provided the corresponding (2S,3R)-α-amino alcohols with good-to-excellent diastereoselectivity. Subsequent chemical transformations provided easy access to the alkynyl side-chain containing (2S,3R)-AHBAs. The utility of the methodology was demonstrated by the stereoselective synthesis of valinoctin A and (2S,3R)-3-amino-2-hydroxydecanoic acid ((2S,3R)-AHDA). Photophysical properties and cell permeability of a pyrene-labeled (2S,3R)-AHBA were also determined.

Undesired versus designed enzymatic cleavage of linkers for liver targeting.

A design for the selective release of drug molecules in the liver was tested, involving the attachment of a representative active agent by an ester linkage to various 2-substituted 5-aminovaleric acid carbamates. The anticipated pathway of carboxylesterase-1-mediated carbamate cleavage followed by lactamization and drug release was frustrated by unexpectedly high sensitivity of the ester linkage toward hydrolysis by carboxylesterase-2 and other microsomal components.

Asymmetric syntheses of APTO and AETD: the ß-amino acid fragments within microsclerodermins C, D, and E.

Efficient asymmetric syntheses of APTO and AETD, the highly functionalized ß-amino acid fragments within microsclerodermins C, D, and E, are reported. The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl (E,E)-7-(triisopropylsilyloxy)hepta-2,4-dienoate and in situ enolate oxidation with (-)-camphorsulfonyloxaziridine, diastereoselective dihydroxylation of a 2,3-syn-γ,δ-unsaturated-α-hydroxy-ß-amino ester derivative under Donohoe conditions, and a Julia-Kocienski olefination were used as the key steps.

[Amino acids in cerebrospinal fluid and plasma: its usefulness in the study of neuropaediatric diseases]. / Aminoacidos en liquido cefalorraquideo y plasma: utilidad en el estudio de las enfermedades neuropediatricas.

INTRODUCTION: Studying the amino acids in cerebrospinal fluid (CSF) is essential in the diagnosis of some neurological diseases and is an important aid in the diagnosis of others. No research has been published in the literature to prove the physiological relationship between the values of amino acids in CSF and plasma in the paediatric population. AIM: To define a set of ratios for amino acids in plasma and CSF in the paediatric population that can be used in daily clinical practice. PATIENTS AND METHODS: The aminograms in plasma and CSF of 105 patients with ages between 0 and 12 months were collected and analysed retrospectively. Aminograms with amino acid values that are considered to be normal according to the reference values of our laboratory were included in the sample. The quantitative analysis of amino acids was performed using high-resolution liquid chromatography and statistical analysis with the software application SPSS 19.0. RESULTS: The mean values, range and standard deviation of the amino acid concentrations in plasma and CSF, together with the CSF/plasma ratios, are reported. Significant correlations were found from 0.6 onwards between different neutral amino acids, above all in those with smaller molecular weights (Thr, Ser, Gly and Ala). CONCLUSIONS: The existence of significant correlations between the different neutral amino acids supports the idea that they share the same transporters in the blood-brain barrier. Standardising the amino acid ratios will make it possible to increase sensitivity in the detection of pathological values in plasma and CSF, to further knowledge of the pathophysiology of neurological diseases and perhaps to describe new aminoacidopathies.

Synthesis and structural study of cyclic 5-aminovaleric acid-linked beta-Ala-beta-Ala dipeptides.

5-Aminovaleric acid and ornithine were evaluated as linkers for the cyclization of beta-dipeptides. Two linked examples of beta-Ala-beta-Ala were prepared by standard coupling methods and their conformations probed by NMR, CD, and computational means. The data suggest that these non- or monosubstituted versions of the target compounds are flexible in solution.

Stereoselective synthesis of the nonproteinogenic amino acid (2S,3R)-3-amino-2-hydroxydecanoic acid from (4S,5S)-4-formyl-5-vinyl-2-oxazolidinone.

(4S,5S)-4-Formyl-5-vinyl-2-oxazolidinone (4b), which is readily obtained via a zinc-silver-mediated reductive elimination of alpha-d-lyxofuranosyl phenyl sulfone (3b), is successfully converted to the naturally occurring, nonproteinogenic amino acid (2S,3R)-3-amino-2-hydroxydecanoic acid (2). Also in this study, a facile "oxazolidinone rearrangement" reaction is uncovered during the attempted formation of the (methylthio)thiocarbonate derivative of the oxazolidinone alcohol 7.