[125I]β-Arbutin

Sodium-glucose co-transporters (SGLTs), particularly SGLT1 and SGLT2, play an active role in glucose uptake by cancer cells and have gained attention as novel therapeutic targets. However, the development of nuclear medicine imaging agents specific to SGLTs has not yet been explored. This study aimed to develop and evaluate radiolabeled glycoside derivatives targeting SGLT1 and SGLT2 for cancer imaging.

β-Arbutin, a structural analog of methyl-α-D-glucopyranoside (MDG) which is SGLTs substrate, and phlorizin, a SGLT2 inhibitor, were selected as glycoside compounds for radioiodination, [¹²⁵I]β-arbutin and [¹²⁵I]phlorizin were synthesized. The accumulation was measured in HEK293 cells transfected overexpress GLUT1, GLUT3, SGLT1, or SGLT2. Subsequent accumulation studies were conducted in LS180 and DLD-1 cancer cell lines, and the gene expression levels were quantified by real-time polymerase chain reaction (PCR). Biodistribution of both radiotracers was examined in tumor-bearing mice.

[¹²⁵I]β-Arbutin had affinity for SGLT1 and SGLT2, whereas [¹²⁵I]phlorizin had affinity for SGLT1 and GLUT3. [¹²⁵I]β-Arbutin accumulated preferentially in SGLT1-high LS180 cells, whereas [¹²⁵I]phlorizin accumulated in GLUT3-high DLD-1 cells. In vivo, [¹²⁵I]β-arbutin exhibited favorable biodistribution with low brain and thyroid accumulation, rapid blood clearance, and high tumor-to-blood ratios in SGLT1-expressing tumors. Although [¹²⁵I]phlorizin also showed low brain and thyroid accumulation, its blood clearance was slower and tumor-to-blood ratios were lower.

[¹²⁵I]β-Arbutin is a promising radiopharmaceutical candidate for imaging cancers with high SGLTs expression.