2-Nitroimidazole-Furanoside Derivatives for Hypoxia Imaging-Investigation of Nucleoside Transporter Interaction, F-Labeling and Preclinical PET Imaging.

The benefits of PET imaging of tumor hypoxia in patient management has been demonstrated in many examples and with various tracers over the last years. Although, the optimal hypoxia imaging agent has yet to be found, 2-nitroimidazole (azomycin) sugar derivatives-mimicking nucleosides-have proven their potential with [F]FAZA ([F]fluoro-azomycin--arabinoside) as a prominent representative in clinical use. Still, for all of these tracers, cellular uptake by passive diffusion is postulated with the disadvantage of slow kinetics and low tumor-to-background ratios.

Stereochemical Course of Methyl Transfer by Cobalamin-Dependent Radical SAM Methyltransferase in Fosfomycin Biosynthesis.

The methyl groups of [ methyl-( S)]- and [ methyl-( R)]-[ methyl-D,T]-l-methionine fed to Streptomyces fradiae were incorporated into fosfomycin, which was chemically degraded to chiral AcONa. The enzymatic test gave the ( S)-configuration for the chiral AcONa derived from methionine with the ( S)-[D,T]methyl group ( F = 31.7) and ( R) for the one derived from methionine with the ( R)-[D,T]methyl group ( F = 83.

Towards the biodegradation pathway of fosfomycin.

Three functionalised propylphosphonic acids were synthesised to study C-P bond cleavage in R. huakuii PMY1. (R)-1-Hydroxy-2-oxopropylphosphonic acid [(R)-5] was prepared by chiral resolution of (±)-dimethyl 1-hydroxy-2-methylallyllphosphonate [(±)-12], followed by ozonolysis and deprotection.

[F]Fluoro-azomycin-2´-deoxy-β-d-ribofuranoside - A new imaging agent for tumor hypoxia in comparison with [F]FAZA.

Introduction: Radiolabeled 2-nitroimidazoles (azomycins) are a prominent class of biomarkers for PET imaging of hypoxia. [F]Fluoro-azomycin-α-arabinoside ([F]FAZA) - already in clinical use - may be seen as α-configuration nucleoside, but enters cells only via diffusion and is not transported by cellular nucleoside transporters. To enhance image contrast in comparison to [F]FAZA our objective was to F-radiolabel an azomycin-2´-deoxyriboside with β-configuration ([F]FAZDR, [F]-β-8) to mimic nucleosides more closely and comparatively evaluate it versus [F]FAZA.

Synthesis and preclinical characterization of 1-(6'-deoxy-6'-[F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-6'-[F]FAZAL) as a positron emission tomography radiotracer to assess tumor hypoxia.

Positron emission tomography (PET) using fluorine-18 (F)-labeled 2-nitroimidazole radiotracers has proven useful for assessment of tumor oxygenation. However, the passive diffusion-driven cellular uptake of currently available radiotracers results in slow kinetics and low tumor-to-background ratios. With the aim to develop a compound that is actively transported into cells, 1-(6'-deoxy-6'-[F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-[F]1), a putative nucleoside transporter substrate, was synthetized by nucleophilic [F]fluoride substitution of an acetyl protected labeling precursor with a tosylate leaving group (β-6) in a final radiochemical yield of 12±8% (n=10, based on [F]fluoride starting activity) in a total synthesis time of 60min with a specific activity at end of synthesis of 218±58GBq/μmol (n=10).

Preparation of nucleosides derived from 2-nitroimidazole and D-arabinose, D-ribose, and D-galactose by the Vorbrüggen method and their conversion to potential precursors for tracers to image hypoxia.

2-Nitroimidazole was silylated using hexaethyldisilazane and then reacted with 1-O-acetyl derivatives of D-arabinose, D-ribose, and D-galactose in acetonitrile at mild temperatures (-20 °C to rt), catalyzed by triethylsilyl triflate (Vorbrüggen conditions). The α-anomer was formed in the former case and the β-anomers in the latter two cases (highly) selectively. When D-arabinose and D-ribose were silylated with tert-butyldiphenylsilyl chloride in pyridine at the hydroxyl groups at C-5 and acetylated at the other ones in a one-pot reaction, mixtures of anomeric 1-O-acetyl derivatives were obtained.

Studies on the biodegradation of fosfomycin: growth of Rhizobium huakuii PMY1 on possible intermediates synthesised chemically.

The first step of the mineralisation of fosfomycin by R. huakuii PMY1 is hydrolytic ring opening with the formation of (1R,2R)-1,2-dihydroxypropylphosphonic acid. This phosphonic acid and its three stereoisomers were synthesised by chemical means and tested as their ammonium salts for mineralisation as evidenced by release of P(i).

NMDA receptor affinities of 1,2-diphenylethylamine and 1-(1,2-diphenylethyl)piperidine enantiomers and of related compounds.

We resolved 1,2-diphenylethylamine (DPEA) into its (S)- and (R)-enantiomer and used them as precursors for synthesis of (S)- and (R)-1-(1,2-diphenylethyl)piperidine, flexible homeomorphs of the NMDA channel blocker MK-801. We also describe the synthesis of the dicyclohexyl analogues of DPEA. These and related compounds were tested as inhibitors of [(3)H]MK-801 binding to rat brain membranes.

On the conversion of structural analogues of (S)-2-hydroxypropylphosphonic acid to epoxides by the final enzyme of fosfomycin biosynthesis in S. fradiae.

2-Hydroxyethyl- and (S)-2-hydroxybutylphosphonic acid were prepared, starting in the latter case from (S)-2-aminobutyric acid. They were fed to cultures of Streptomyces fradiae producing fosfomycin. Only the latter (150 microg/mL of medium) was converted to the ethyl analogue of fosfomycin, isolated as 2-amino-1-hydroxybutylphosphonic acid (3%) in admixture with 2-amino-1-hydroxypropylphosphonic acid (97%) derived from fosfomycin.