Abstract
Lipocalin-type prostaglandin D synthase (L-PGDS) has been correlated with the progression of neurological disorders. The present study aimed at evaluating the imaging potency of a glutathione conjugate of fluorine-18-labeled fluorobutyl ethacrynic amide ([18F]FBuEA-GS) for brain tumors. Preparation of [18F]FBuEA-GS has been modified from the -4-tosylate derivative via radiofluorination in 5% radiochemical yield. The mixture of nonradioactive FBuEA-GS derived from a parallel preparation has be resolved to two isomers in a ratio of 9∶1 using analytic chiral reversed phase high performance liquid chromatography (RP-HPLC). The two fluorine-18-labeled isomers purified through nonchiral semipreparative RP-HPLC as a mixture were studied by assessing the binding affinity toward L-PGDS through a gel filtration HPLC, by analyzing radiotracer accumulation in C6 glioma cells, and by evaluating the imaging of radiotracer in a C6 glioma rat with positron emission tomography. The inhibition percentage of the production of PGD2 from PGH2 at the presence of 200 µM of FBuEA-GS and 4-Dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)butyl]piperidine (AT-56) were 74.1±4.8% and 97.6±16.0%, respectively. [18F]FBuEA-GS bound L-PGDS (16.3–21.7%) but not the isoform, microsomal prostaglandin E synthase 1. No binding to GST-alpha and GST-pi was observed. The binding strength between [18F]FBuEA-GS and L-PGDS has been evaluated using analytic gel filtration HPLC at the presence of various concentrations of the cold competitor FBuEA-GS. The contrasted images indicated that the radiotracer accumulation in tumor lesions is probably related to the overexpression of L-PGDS.
Highlights
According to Central Brain Tumor Registry of United States, brain tumor has emerged as the second and fifth to leading cause to death of adult male and of adult female, respectively, aging from 20 to 39 [1]
We found that t-BuOH did not improve the radiochemical yield, no failure was encountered during the fluorination. [18F]FBuEA-GS 3 could be formed via the conjugation of [18F]FBuEA 2 with GSH by merely adjusting pH = 8.0
Nonradioactive FBuEA-GS 3 obtained from a parallel experiment could be resolved into two isomers in a ratio of 9:1 using analytic chiral HPLC (Fig. 2a)
Summary
According to Central Brain Tumor Registry of United States, brain tumor has emerged as the second and fifth to leading cause to death of adult male and of adult female, respectively, aging from 20 to 39 [1]. Whereas magnetic resonance imaging (MRI) is a useful clinical setting for noninvasive grading of brain tumor [2], evaluation of the treatment effects in malignant brain tumors is challenging [3]. Detection of those areas where the tumor progresses into the neighboring tissue highly depends on the extent and activity of this proliferation zone. These regions cannot often be distinguished from edema or necrosis by morphologic imaging modalities such as CT or MRI, . Recent study of PET showed that a larger tumor volume could be detected using both [18F]FLT and [11C]methionine than that using gadolinium-enhanced MRI because increased transport and phosphorylation were always accompanied with the brain blood barrier disruption
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