Design, Synthesis, and Evaluation of a Novel ^99m Tc-Labeled Small Molecule Inhibitor (Lapatinib)-Based SPECT Tracer Targeting HER2

Radiolabeled human epidermal growth factor receptor 2 (HER2) tracers are important tools for the accurate clinical diagnosis and treatment of HER2-positive tumors. The aim of this study was to investigate the potential of small molecule inhibitors (lapatinib) as target groups for novel radiotracers targeting HER2. Twelve stable radiotracers were prepared by chelation with different coligands. The relationships between the linker and the combination of coligands with pharmacodynamics were systematically evaluated. [^99mTc]Tc-Lapa-HYNIC-TPPTS exhibits the most favorable pharmacokinetic properties, as it can stably bind to the active pocket of the HER2 protein. Both <i>in vitro</i> and <i>in vivo</i> studies demonstrated its high targeting specificity toward HER2. SPECT images of [^99mTc]Tc-Lapa-HYNIC-TPPTS in HER2-positive model mice revealed that it can effectively locate tumors. This study is the first attempt at a ^99mTc-labeled small-molecule inhibitor tracer targeting HER2, showing great potential for applications in the diagnosis of HER2-positive cancers.