6-Deoxy-6-[¹³¹I]iodo-<small>L</small>-ascorbic Acid for the <i>in Vivo</i> Study of Ascorbate: Autoradiography, Biodistribution in Normal and Hypolipidemic Rats, and in Tumor-Bearing Nude Mice

Abstract

Over the past few decades, a number of radiopharmaceuticals for noninvasive imaging of the adrenal glands by the nuclear imaging technique have been evolved, designed by targeting specific metabolic or synthetic processes within the gland.1,2) Among the current developments and the expansion of new molecular imaging modalities and specific probes, adrenal scintigraphy using more specific radiotracers to obtain functional information for tissue characterization is still challenging. 3,4)The adrenal gland is among the organs with the highest concentration of L-ascorbic acid (AsA) in the body and is particularly sensitive to deficiencies of AsA.5) It is well known that AsA is an important cofactor required both in catecholamine biosynthesis and in adrenal steroidogenesis, and that it functions as a water-soluble antioxidant in the adrenal gland. [5][6][7][8][9] The cellular uptake of AsA and its distribution in cells are important factors that determine its inherent activity. Studies of tissue distribution of radioactivity in animals after injection of 14 C-labeled AsA ( 14 C-AsA) were reported in the 1960s, showing a remarkable uptake of radioactivity in the adrenal glands, pituitary glands and parotid glands.10-12) Diagnostic application of AsA as a radiotracer for imaging the adrenals, however, remains to be limited by relatively high accumulations of 14 C-AsA in the liver and kidneys. 13)Recent biochemical studies have demonstrated that AsA is taken up into cells by the sodium-dependent vitamin C transporter (SVCT-1 and -2), whereas oxidized vitamin C (dehydroascorbic acid) is transported via glucose transporters. [14][15][16][17][18][19] SVCT-1 is expressed in epithelial organs such as the liver and kidneys, whereas SVCT-2 is found in the adrenal glands and lungs. [14][15][16][17][18][19] In particular, SVCT-2 is primarily responsible for the uptake of AsA from blood circulation into the adrenal cells. [14][15][16][17][18][19] The adrenals have been shown to have the largest falls in the AsA levels in mice with a deficiency of 20) and the influence of the depletion of tissue AsA on tissue catecholamines was found to be most prominent in the adrenals. 21,22) In addition, it has recently been shown that overexpression of adrenal SVCT-2 mRNA in diabetic mice resulted in increased uptake of AsA. 23) Thus, it is most likely that the AsA transport mechanism plays an important role in the pathologic processes of the adrenals. 24) We became interested in the possibility that appropriate structural AsA analogs with specific transport characteristics, if possessing favorable in vivo distribution properties, might be used as tracer agents for the visualization of biochemical events associated with the action of AsA in the adrenal glands. Several AsA analogs labeled with 18 F, 131 I, 125 I, or 99m Tc were prepared and their potential imaging characteristics were evaluated in animals. [25][26][27][28][29][30][31] 6-Deoxy-6-iodo-L-ascorbic acid (6-IAsA) has been shown to be an effective inhibitor of AsA transport, with tran...

5-O-(4-[125I]Iodobenzyl)-L-ascorbic Acid: Electrophilic Radioiodination and Biodistribution in Mice

“…There was a somewhat slower clearance of the radioactivity from the blood when compared to 6-18 FAsA 10-13) and 6-131 IAsA 14,15) studied previously. The accumulation of radioactivity in selected organs was highest in the kidneys>liver>lungs>adre nals>heart at 2 min postinjection and then the radioactivity levels gradually decreased with time, similar to those seen for [6][7][8][9][10][11][12][13][14][15][16][17][18] FAsA and 6-131…”

“…Moreover, tumor accumulation in the fibrosarcoma was not significant, also similar to those of [6][7][8][9][10][11][12][13][14][15][16][17][18] FAsA and IAsA. Recent studies have shown that high-grade tumor tissue has reduced capacity to accumulate AsA relative to normal tissue.…”

“…26,27) We previously reported that IAsA uptake by the adrenal glands of rats was significantly inhibited by pretreatment with sulfinpyrazone (1.5 μg/g per animal) in vivo. 15) In this study a similar experiment was carried out to see the response to sulfinpyrazone-treatment for […”

“…In previous studies, we reported the synthesis of several AsA analogs, focusing on the introduction of radioisotopes such as 18 F and 131 I at the C-6 position of the AsA core, and their potential imaging characteristics were also evaluated in rodents. Among them, 6-deoxy-6-[ 18 F]fluoro-L-ascorbic acid (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) FAsA) [10][11][12][13] and 6-deoxy-6-[ 131 I]iodo-L-ascorbic acid IAsA) 14,15) showed the expected distribution of highest uptake in the adrenal glands in rodents, a neuroendocrine organ that is known to highly express the SVCT-2 transporter, 16) thus demonstrating their suitability as radiotracer analogs of AsA. However, the application of these radiotracers as brain-targeted imaging probes for in vivo studies was found to be limited because of their poor delivery from blood circulation into the brain.…”

Vitamin C Transporters in Cancer: Current Understanding and Gaps in Knowledge

“…Data in mice showed increased radioactive ascorbate uptake in adrenal glands, compared to adrenocortical or adrenal medulla tumors, and adrenal uptake was sensitive to the ascorbate transport blocking agent sulfinpyrazone (67). In a mouse neuroblastoma cell line, SVCT2 was found to have two different transport kinetics ( K m of 13 and 105 µM), and transport could be inhibited with flavonoids (68).…”