Influence of Linker Molecules on the Biodistribution Characteristics of ^99mTc-labeled Mannose Derivatives with an Isocyanide-Coordinated Group

A hallmark of cancer cells is their increased glucose demand, which is mediated by glucose transporters (GLUTs). Mannose is imported into cells via GLUTs, thereby prompting the selection of mannose as the targeting molecule for designing radioactive derivatives for tumor imaging. In this study, five ^99mTc-labeled mannose derivatives were prepared and evaluated <i>in vitro</i> and <i>in vivo</i>. The derivatives were conjugated with an isonitrile group and different linkers, including (CH₂)₅-_Dpro, (CH₂)₆-_Dpro, (CH₂)₇-_Dpro, (CH₂)₅-_Lpro, and (CH₂)₆-_Lpro. All five radioactive compounds exhibited hydrophilicity and <i>in vitro</i> stability. A comparative biodistribution study demonstrated that probes modified with _D-proline exhibited greater uptake in tumors than those modified with _L-proline. [^99mTc]Tc-<b>L1</b> exhibited the highest accumulation in the tumor and the most favorable tumor-to-nontarget ratios. SPECT/CT imaging results of [^99mTc]Tc-<b>L1</b> demonstrated clear accumulation and visualization at the tumor site. Blocking studies in cells and mice bearing S180 tumors revealed that [^99mTc]Tc-<b>L1</b> was transported into cancer cells via a GLUT-mediated mechanism. These findings suggest that [^99mTc]Tc-<b>L1</b> is a promising probe for SPECT tumor imaging and that linker molecules significantly affect biodistribution characteristics.