Fluoroazomycin arabinoside (FAZA): synthesis,2H and3H-labelling and preliminary biological evaluation of a novel 2-nitroimidazole marker of tissue hypoxia

Abstract

1‐α‐D‐(5‐Fluoro‐5‐deoxyarabinofuranosyl)‐2‐nitroimidazole (fluoroazomycin arabinoside, FAZA) 6, a putative PET imaging agent when labelled with 18F, was synthesized by fluorination of 1‐α‐D‐(2,3‐di‐O‐acetylarabinofuranosyl)‐2‐nitroimidazole 3 with DAST followed by deprotection. The C‐5′‐deuterated and tritiated analogues were prepared by NaCNBD3 or NaCNBT3 reduction of the protected C‐5′‐carbonyl intermediate 5, followed by C‐5′ fluorination and deprotection, to afford C‐5′ deuterated and C‐5′ tritiated FAZA, respectively. Preliminary in vivo biodistribution studies in a murine tumour model, and pharmacokinetic studies in rats indicated that 3H‐FAZA has biodistribution, tumour uptake and pharmacokinetic properties similar to those of 123I‐IAZA, a clinically‐proven radiopharmaceutical for SPECT‐imaging of hypoxic tissues. Copyright © 1999 John Wiley & Sons, Ltd.

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

“…The crude product was purified by flash chromatography (at first hexanes/EtOAc, 1:1, R f 0.08, and then 1:5) to give α-23 (0.113 g, 84%) as a crystalline solid: mp 115À116 °C (C 2 H 4 Cl 2 /i-Pr 2 O) (lit. 26 13 C NMR data agree with those of the literature. 25 1-α-[2 0 ,3 0 -Di-O-acetyl-5 0 -O-(4-toluenesulfonyl)-D-arabinofuranosyl]-2-nitroimidazole (α-7).…”

“…Under optimized conditions, a mixture of NI-TES and 14 in CH 3 CN was cooled to −20 °C, and 1 equiv of a 1 M solution of TfOTES in 1,2-C 2 H 4 Cl 2 was added dropwise. Stirring was continued while the reaction mixture was allowed to warm to −8 °C within 3 h. Extractive workup and flash chromatography furnished the α-nucleoside( 26 ) α- 15 in 72% yield beside some starting material and a trace of the β-anomer detected by TLC, which was not isolated (Scheme 3 ). Anticipating later results, α- 15 was converted in two steps into precursor α- 7 .…”

Synthesis, Radiosynthesis, and in vitro Studies on Novel Hypoxia PET Tracers Incorporating [18F]FDR

“…Partition coefficients (P) of non-radioactive compounds 13 a-f were determined using the RP-HPLC method [28,29] and log P values were calculated ( Table 1). The log P values of AZA (À 0.28), FAZA (0.04), FMISO (0.4), IAZA (0.70) and BnOH (1.10), reported in literature, [28,30,31] were used as reference values to extrapolate log P values of 13 a-f. The radiosynthesis of the target fluorinated tracers [ 18 F]-15 a-f ( Figure 2) was addressed next.…”

2-Nitroimidazole-Furanoside Derivatives for Hypoxia Imaging—Investigation of Nucleoside Transporter Interaction, 18F-Labeling and Preclinical PET Imaging

“…FAZA [23,24], α -FAZDR and β -FAZDR [13] were prepared by known procedures; for β -FAZA, a novel synthesis route was developed, although β -FAZA is a known compound [14]. Figure 1 gives the structures of the non-radioactive fluorinated 2-nitroimidazole sugars that were synthesized and evaluated for their interaction with human nucleoside transporters (see Section 2.3).…”