Abdallah Deyine

Design of silicon-based misonidazole analogues and 18F-radiolabelling

INTRODUCTION Development of new (18)F-labeled tracers for positron emission tomography (PET) imaging is increasingly important. Herein, we described the synthesis of silicon analogues of [(18)F]fluoromisonidazole in order to develop new radiolabelled compounds for the detection of tumour hypoxic domain. Their stabilities and their in vivo biodistribution were evaluated. METHODS (18)F-labeled silicon-based misonidazole analogues were synthesized by alkylating 2-nitroimidazole with alkyloxy-(3-chloropropyl)dialkyl or diarylsilane. These intermediates were labeled with [(18)F]F(-) with a mixture of K(18)F and Kryptofix (K222) in acetonitrile as standard condition. PET imaging was performed using a dedicated small animal PET scanner. RESULTS (18)F-labeled silicon-based misonidazole analogues were easily synthesized in three steps. The hydrolytic and radiolytic stability of these new fluorosilanes depend on the steric hindrance at the silicon center. Indeed, partial uptake of dimethylfluorosilane [(18)F]2a(1-(3-(Fluorodimethylsilyl)propyl)-2-nitro-1H-imidazole) in tumor hypoxic area was observed but defluorination also appeared. Moreover, PET studies indicated that, owing to its high lipophilicity, the most stable dinaphtylfluorosilane [(18)F]2d is retained mainly by the lungs. CONCLUSION We have described an efficient and versatile approach for the synthesis of (18)F-labeled, silicon-based misonidazole analogues. PET imaging of one of these compounds revealed that hypoxia could be detected. Controlling the biodistribution of (18)F-labeled silicon-based misonidazole analogues will require additional studies.

2-Alkoxy-3-oxoalkyl-tetrahydropyrans and -tetrahydrofurans: versatile intermediates in heterocyclic synthesis

A new Lewis acid-catalysed Michael-type addition of heterocyclic enol ethers to hemiacetal vinylogues 1 or to enones in the presence of a hydroxylic compound is described. The 1,5-keto acetals 3 so obtained have been studied with a view to synthetic applications. Acidic hydrolysis of compounds 3 leads in most cases to annulation products 9 in a stereocontrolled manner. Organometallic addition, hydride reduction or reductive amination of 1,5-keto acetals 3 afford, in good yields, the hydroxy acetals 12(and cyclisation products 13) and amino acetals 18, respectively. Acidic treatment of these compounds gave access to oxa- and aza-annulation products 13, 17 and 19 by an efficient kinetically controlled heterocyclisation process. These products can be obtained with high cis-junction selectivities as established by NMR spectroscopy and confirmed by equilibration studies.

A FACILE ISOMERIZATION PROCEDURE FOR THE ACCESS TO THERMODYNAMIC SILYL ENOL ETHERS

Abstract Efficient access to thermodynamically favoured silyl enol ethers deriving from α,α′-dienolizable ketones was produced via easy-made NEt3HCl-mediated isomerization of a regioisomeric mixture of O-silylated products. † deceased on 7 may 1997 § Present adress: Laboratoire de Synthese Organique, associe au CNRS, Universite du Maine, Avenue Olivier Messiaen, B.P. 9 F-72085 Le Mans (France)