Abstract
P574
Introduction: Transient receptor potential vanilloid 1 (TRPV1) is an ion channel present on sensory neurons and mainly serves as a multimodal sensor of noxious stimuli which would trigger counteractive measures to avoid pain and injury. The purpose of our study was to synthesize new PET-radioligands for TRPV1 and elucidate biological evaluation of [11C]- as well as [18F]-labeled analogues.
Methods: TRPV1-targeted compounds were synthesized by modifying the structure of SB366791, a pharmaceutically representative TRPV1 antagonist, which was previously reported by Veghel DV et al. In order to avoid amide–iminol tautomerization, structurally supported N-methylated amides (i.e., 3-alkoxy-substitued N-meythylamide derivatives of SB366791) were evaluated using a Ca2+ influx assay, in which cells expressed recombinant TRPV1 in the presence of 1.0 μM capsaicin. Ehrlich Ascites Carcinoma (EAC) cells were cultivated and transplanted in subcutaneous tissue of rats. PET images of rats were reconstructed with the statistical-maximum a-posteriori probability algorithm and summated from 5 to 60 min after the bolus injection of the tracers.
Results: The antagonistic activities of N-(3-methoxyphenyl)-N-methyl-4-chlorocinnamamide (RLC-TV1004) and N-{3-(3-fluoropropoxy) phenyl}-N-methyl-4-chlorocinnamamide (RLC-TV1006) were found to be approximately three-fold higher (IC50: 1.3 μM and 1.1 μM, respectively) than that of SB366791 (IC50: 3.7 μM). Using the [11C]- or [18F]-labeled derivatives, explorative PET imaging trials were performed in rats. Biodistribution of cerebral cortex, striatum, hippocampus, thalamus, hypothalamus, liver, intestine, urinary bladder, and skin was identified (Fig). Transplanted tumor tissue could be also visualized.
Conclusions: The 3-methoxy and 3-fluoroalkoxy substituents reveals favorable radioactive [11C]methoxy- or [18F]fluoroalkoxy-incorporated tracers for visualization of in vivo PET.
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.