Development of fluorinated naphthofluoresceins for Cerenkov imaging.

In this paper, we report the synthesis and characterization of fluorinated derivatives of naphthofluorescein (NF), a fluorescent pH-sensitive probe that can be used for functional Cerenkov imaging. The compounds were prepared using electrophilic fluorination with dilute fluorine gas under acidic conditions. The fluorination of the NF molecule occurred in the positions to the hydroxyl moiety, producing mono-, di-, and tri-substituted derivatives.

Synthesis of pH indicators for Cerenkov imaging by electrophilic substitution of bromine by fluorine in an aromatic system.

Direct electrophilic fluorination using molecular fluorine gas is used in organic synthesis to create novel fluorine-containing compounds with potential beneficial activity that could not be obtained by nucleophilic substitution. In this paper, we report a novel electrophilic substitution of bromine by fluorine in an aromatic system. The mechanism of this type of fluorination was explored using the reaction between bromothymolsulfonphthalein (Bromothymol Blue) and dilute fluorine gas under acidic conditions.

Synthesis of F-18 labeled resazurin by direct electrophilic fluorination.

We present the synthesis and characterization of F18-labeled fluorinated derivatives of resazurin, a probe for cell viability. The compounds were prepared by direct fluorination of resazurin with diluted [F18]-F gas under acidic conditions. The fluorination occurs into the -positions to the hydroxyl group producing various mono-, di-, and trifluorinated derivatives.

Cerenkov-specific contrast agents for detection of pH in vivo.

Unlabelled: We report the design, testing, and in vivo application of pH-sensitive contrast agents designed specifically for Cerenkov imaging. Radioisotopes used for PET emit photons via Cerenkov radiation. The multispectral emission of Cerenkov radiation allows for selective bandwidth quenching, in which a band of photons is quenched by absorption by a functional dye.

Synthesis of F-labeled phenolphthalein and naphtholphthalein.

The fluorination of phenolphthalein and naphtholphthalein was performed with diluted fluorine gas under acidic conditions. For both compounds we observed an electrophilic fluorination into ortho position to the hydroxyl group. Through the use of this reaction we synthesized and characterized mono-and difluorinated derivatives of phenolphthalein and naphtholphthalein.

Synthesis and characterization of fluorinated derivatives of cresolsulfonphthalein.

The reaction between dilute fluorine gas and cresolsufonphthalein in acetic acid was investigated. The mono-, di-, and trifluorinated cresolsufonphthalein derivatives were isolated and characterized. These compounds possessed the properties of pH indicators with biologically relevant pK values (6.

Direct fluorination of phenolsulfonphthalein: a method for synthesis of positron-emitting indicators for in vivo pH measurement.

We report a reaction of direct electrophilic fluorination of phenolsulfonphthalein at mild conditions. This reaction affords the synthesis of novel positron-emitting (18)F-labeled pH indicators. These compounds are useful for non-invasive in vivo pH measurement in biological objects.

Biodistribution and dosimetry of (18)F-EF5 in cancer patients with preliminary comparison of (18)F-EF5 uptake versus EF5 binding in human glioblastoma.

Purpose: The primary purpose of this study was to assess the biodistribution and radiation dose resulting from administration of (18)F-EF5, a lipophilic 2-nitroimidazole hypoxia marker in ten cancer patients. For three of these patients (with glioblastoma) unlabeled EF5 was additionally administered to allow the comparative assessment of (18)F-EF5 tumor uptake with EF5 binding, the latter measured in tumor biopsies by fluorescent anti-EF5 monoclonal antibodies.

Methods: (18)F-EF5 was synthesized by electrophilic addition of (18)F(2) gas, made by deuteron bombardment of a neon/fluorine mixture in a high-pressure gas target, to an allyl precursor in trifluoroacetic acid at 0° then purified and administered by intravenous bolus.

The radiation response of cells from 9L gliosarcoma tumours is correlated with [F18]-EF5 uptake.

Purpose: Tumour hypoxia affects cancer biology and therapy-resistance in both animals and humans. The purpose of this study was to determine whether EF5 ([2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide]) binding and/or radioactive drug uptake correlated with single-dose radiation response in 9L gliosarcoma tumours.

Materials And Methods: Twenty-two 9L tumours were grown in male Fischer rats.

Catalysis of fluorine addition to double bond: an improvement of method for synthesis of (18)F PET agents.

Catalysis for reaction of electrophilic fluorine addition to a fluorinated double bond is described. The presence of small amounts of iodine, bromine, or boron trifluoride increases an overall product yield and degree of fluorine incorporation, making the reaction a more efficient method for preparation of (18)F positron emission tomography agents. A possible mechanism of catalytic action of iodine is discussed.

Detection of reactive oxygen species via endogenous oxidative pentose phosphate cycle activity in response to oxygen concentration: implications for the mechanism of HIF-1alpha stabilization under moderate hypoxia.

The oxidative pentose phosphate cycle (OPPC) is necessary to maintain cellular reducing capacity during periods of increased oxidative stress. Metabolic flux through the OPPC increases stoichiometrically in response to a broad range of chemical oxidants, including those that generate reactive oxygen species (ROS). Here we show that OPPC sensitivity is sufficient to detect low levels of ROS produced metabolically as a function of the percentage of O2.

Mutation in G6PD gene leads to loss of cellular control of protein glutathionylation: mechanism and implication.

More than 400 million people are susceptible to oxidative stress due to glucose-6-phosphate dehydrogenase (G6PD) deficiency. Protein glutathionylation is believed to be responsible for loss of protein function and/or cellular signaling during oxidative stress. To elucidate the implications of G6PD deficiency specifically in cellular control of protein glutathionylation, we used hydroxyethyldisulfide (HEDS), an oxidant which undergoes disulfide exchange with existing thiols.