Abstract
1021
Objectives: Potassium channels are ubiquitous proteins involved in a wide variety of cell functions. While they have been most commonly studied regarding cell excitability, assessment of their roles in angiogenesis, cell proliferation and migration has propelled the recent emergence of K+ channels as potential biomarkers for cancer. A large body of data indicates that altered expression of voltage-dependent K+ (Kv) channels is found in several types of cancer cells and tumors. For instance, potassium channels Kv10.1 and Kv11.1 have been implicated in tumor angiogenesis, cell proliferation and migration1,2 while others like Kv1.1, Kv1.3 and Kv1.5 seem to have relevant roles in the regulation of apoptotic processes.3 Furthermore, aberrant expression of channels like Kv1.3 and Kv1.5 has been differentially correlated to tumorigenic state and degree of malignancy in different cancer cells, suggesting the possibility to use these potassium channels as tumoral biomarkers as well as prognostic and diagnostic indicators.4 [18F]3-fluoro-4-aminopyridine ([18F]3F4AP) is a radiofluorinated analog of the general K+ channel blocker 4-aminopyridine that was recently developed to image changes in K+ channel expression in neurological disorders like multiple sclerosis.5 The binding nature of [18F]3F4AP to channels in the Kv1 family led us to investigate this novel radioligand as a tool to image K+ channels as potential tumor markers in different types of cancer. To this end, [18F]3F4AP was synthesized according to previous reports from a nicotinic acid precursor6 and used to image mouse xenograft models of three human cancers.
Methods: Briefly, methyl-3-nitroisonicotinate was 18F-radiolabeled, followed by ester hydrolysis and subsequent conversion to the amine tracer via the Yamada-Curtius rearrangement reaction. Nude mice were subcutaneously inoculated with glioblastoma (U-118), squamous lung cancer (H-520) or melanoma (A-375) cells on the right or left flank. Dynamic PET combined with computed tomography (PET/CT) imaging was performed for 60 min after tail vein injection of 200 μCi of [18F]3F4AP 16 to 40 days post tumor inoculation.
Results: [18F]3F4AP was produced with molar activity (> 1 Ci/umol) and high radiochemical purity (> 95%). Preliminary analysis of PET results shows a low but differential tumor uptake of the [18F]3F4AP radiotracer when comparing the different cancer lines. Radiotracer uptake varied within tumor type: U-118 (glioblastoma) tumors showed homogenous distribution of the tracer whereas H-520 (lung cancer) and A-375 (melanoma) showed lower uptake in the core than in the periphery. Furthermore, analysis of the time-activity curves shows slow tumoral uptake of the tracer when compared to other tissues. Further studies are ongoing to characterize tracer binding and compare it with K+ channel levels. Research support: T32EB013180 (G.E.F.), R00EB020075 (P.B.)