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Development and Preclinical Evaluation of a Selinexor-Derived Radiotracer [68Ga]Ga-NOTA-Selinexor for Imaging XPO1
Xinlin Zhong1,2,3, Junjie Yan2, Chen Su4
1School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, P. R. China.
Abstract:
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.
Insights
A new PET tracer, Gallium-68 labeled NOTA-selinexor, improves imaging of XPO1 expression in multiple myeloma by enhancing tumor contrast and ratios. This tracer offers a promising tool for diagnosing and monitoring MM.
Area of Science:
- Nuclear Medicine
- Radiochemistry
- Oncology
Background:
- Selinexor is an FDA-approved XPO1 inhibitor for multiple myeloma (MM).
- Previous attempts at 18F-labeling selinexor for PET imaging resulted in poor contrast due to high lipophilicity.
- Improved PET tracers are needed for noninvasive evaluation of XPO1 expression in MM.
Purpose of the Study:
- To develop and evaluate a novel PET tracer, [68Ga]Ga-NOTA-selinexor, for imaging XPO1 expression in MM.
- To assess the tracer's radiochemical properties, stability, and in vivo performance in MM xenograft models.
Main Methods:
- Selinexor was conjugated to a NOTA chelator via an ethylene spacer.
- Radiolabeling with Gallium-68 (68Ga) was performed.
- Radiochemical yield, purity, and molar activity were determined.
- Molecular docking, lipophilicity, and stability studies were conducted.
- In vivo PET imaging was performed in MM xenograft models.
Main Results:
- [68Ga]Ga-NOTA-selinexor was synthesized with >95% radiochemical yield and ~96% purity.
- The tracer demonstrated a hydrophilic profile (logD7.4 = -0.91) and good stability.
- Molecular docking confirmed retained binding affinity to XPO1.
- In vivo imaging showed a significantly higher tumor-to-muscle ratio (~4.4) compared to [18F]selinexor (~2.1).
- Superior imaging contrast was observed with [68Ga]Ga-NOTA-selinexor.
Conclusions:
- [68Ga]Ga-NOTA-selinexor is a promising hydrophilic PET tracer for noninvasive evaluation of XPO1 expression in MM.
- The improved imaging characteristics offer potential for precise diagnosis and treatment assessment in MM.
- This tracer represents a significant advancement over previous imaging agents for MM.
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