Dataset Information

Preparation of o-Fluorophenols from Nonaromatic Precursors: Mechanistic Considerations for Adaptation to Fluorine-18 Radiolabeling.

ABSTRACT: The preparation of fluorine-18 labeled o-fluorophenols at high specific activity is challenging and requires use of [(18)F]fluoride ion as the radioisotope source. As a novel, alternative approach, we found that treatment of ?-diazocyclohexenones with Selectfluor and Et3N·3HF followed by HF elimination and tautomerization afforded o-fluorophenols regioselectively and rapidly. To adapt this chemistry to (18)F radiolabeling, using bromine electrophiles in place of Selectfluor gave the o-fluorophenol via an ?-bromo-?-fluoroketone intermediate in lower but still reasonable yields.

SUBMITTER: Yasui N

PROVIDER: S-EPMC4795842 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Preparation of o-Fluorophenols from Nonaromatic Precursors: Mechanistic Considerations for Adaptation to Fluorine-18 Radiolabeling.

Yasui Norio N Mayne Christopher G CG Katzenellenbogen John A JA

Organic letters 20151104 22

The preparation of fluorine-18 labeled o-fluorophenols at high specific activity is challenging and requires use of [(18)F]fluoride ion as the radioisotope source. As a novel, alternative approach, we found that treatment of α-diazocyclohexenones with Selectfluor and Et3N·3HF followed by HF elimination and tautomerization afforded o-fluorophenols regioselectively and rapidly. To adapt this chemistry to (18)F radiolabeling, using bromine electrophiles in place of Selectfluor gave the o-fluorophen ...[more]

PMID: 26536250

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Project description:UNLABELLED: BACKGROUND:To date, few PET tracers for in vivo labeling of red blood cells (RBCs) are available. In this study, we report the radiosynthesis and in vitro and in vivo evaluation of 11C and 18F sulfonamide derivatives targeting carbonic anhydrase II (CA II), a metallo-enzyme expressed in RBCs, as potential blood pool tracers. A proof-of-concept in vivo imaging study was performed to demonstrate the feasibility to assess cardiac function and volumes using electrocardiogram (ECG)-gated positron emission tomography (PET) acquisition in comparison with cine magnetic resonance imaging (cMRI) in rats and a pig model of myocardial infarction. METHODS:The inhibition constants (Ki) of CA II were determined in vitro for the different compounds by assaying CA-catalyzed CO2 hydration activity. Binding to human RBCs was estimated after in vitro incubation of the compounds with whole blood. Biodistribution studies were performed to evaluate tracer kinetics in NMRI mice. ECG-gated PET acquisition was performed in Wistar rats at rest and during pharmacological stress by infusing dobutamine at 10 ?g/kg/min and in a pig model of myocardial infarction. Left ventricular ejection fraction (LVEF) and volumes were compared with values from cMRI. RESULTS:The Ki of the investigated compounds for human CA II was found to be in the range of 8 to 422 nM. The fraction of radioactivity associated with RBCs was found to be ?90% at 10- and 60-min incubation of tracers with heparinized human blood at room temperature for all tracers studied. Biodistribution studies in mice indicated that 30% to 67% of the injected dose was retained in the blood pool at 60 min post injection. A rapid and sustained tracer uptake in the heart region with an average standardized uptake value of 2.5 was observed from micro-PET images. The LVEF values obtained after pharmacological stress in rats closely matched between the cMRI and micro-PET values, whereas at rest, a larger variation between LVEF values obtained by both techniques was observed. In the pig model, a good agreement was observed between PET and MRI for quantification of left ventricular volumes and ejection fraction. CONCLUSIONS:The 11C and 18F sulfonamide derivatives can be used for efficient in vivo radiolabeling of RBCs, and proof-of-concept in vivo imaging studies have shown the feasibility and potential of these novel tracers to assess cardiac function.

Dataset Information

Preparation of o-Fluorophenols from Nonaromatic Precursors: Mechanistic Considerations for Adaptation to Fluorine-18 Radiolabeling.

Publications

Preparation of o-Fluorophenols from Nonaromatic Precursors: Mechanistic Considerations for Adaptation to Fluorine-18 Radiolabeling.

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