Development and Preclinical Evaluation of a Selinexor-Derived Radiotracer [68Ga]Ga-NOTA-Selinexor for Imaging XPO1 Expression in Multiple Myeloma.

Selinexor, an FDA-approved XPO1 inhibitor for relapsed or refractory multiple myeloma (MM), has been explored as a precursor for isotopologically 18F-labeling to enable PET imaging of XPO1 expression in MM. However, low tumor-to-muscle (T/M) ratio and poor imaging contrast were observed due to high tracer's lipophilicity. In the present study, selinexor was conjugated to a NOTA chelator via an amide-linked two-carbon (ethylene) spacer to generate the target compound NOTA-selinexor. Subsequent radiolabeling with 68Ga successfully yielded [68Ga]Ga-NOTA-selinexor in over 95% radiochemical yield (RCY) and approximately 96% radiochemical purity (RCP), as well as a molar activity of 12.08 ± 1.37 GBq/μmol. Molecular docking analysis confirmed that the unlabeled precursor retained binding affinity toward XPO1. Furthermore, the radiotracer possessed a hydrophilic profile (log D7.4 = -0.91 ± 0.07) and demonstrated favorable stability under physiological conditions. In vivo PET imaging in MM xenograft models demonstrated that [68Ga]Ga-NOTA-selinexor achieved superior imaging contrast and a significantly higher T/M ratio (∼4.4) compared to previously reported [18F]selinexor (∼2.1). Taken together, these findings suggest that [68Ga]Ga-NOTA-selinexor serves as a valuable PET tracer for noninvasively evaluating XPO1 expression in vivo, highlighting its potential for both precise diagnosis and treatment assessment in MM.