PET imaging of XPO1 engagement with [18F]selinexor: A pharmacodynamic theranostic strategy for multiple myeloma.

Exportin 1 (XPO1), a nuclear export protein frequently overexpressed in multiple myeloma (MM), represents a validated therapeutic target. However, noninvasive imaging approaches capable of assessing XPO1 engagement and pharmacodynamic modulation during therapy remain limited. Here, we present the radiosynthesis and preclinical evaluation of [18F]selinexor, an XPO1-targeted positron emission tomography (PET) radiotracer derived from the clinically used drug selinexor via an 18F/19F isotope exchange method. This labeling approach preserves the parent drug's molecular structure and pharmacological characteristics, enabling in vivo tracking of selinexor. [18F]Selinexor was synthesized with a radiochemical yield of 23.9 ± 4.1% and molar activity of 0.41 ± 0.08 GBq/μmol. The tracer exhibited favorable stability, XPO1-specific binding, and tumor retention. PET imaging and pharmacokinetic analysis demonstrated rapid systemic distribution followed by slow elimination, closely consistent with known pharmacokinetics of selinexor. Predominant hepatobiliary clearance and prolonged blood retention supported optimal tumor uptake at delayed imaging time points, with tracer uptake peaking at 3 h post-injection in MM.1S (2.92 ± 0.30% ID/g) and NCI-H929 (2.50 ± 0.18% ID/g) xenografts. Uptake was markedly reduced upon blocking, confirming the tracer's in vivo specificity. During therapeutic intervention, repeated selinexor administration effectively suppressed tumor growth and was accompanied by a progressive reduction in tumor uptake from 3.03 ± 0.25% ID/g (day 0) to 0.93 ± 0.13% ID/g (day 15). Notably, this reduction in uptake occurred independently of changes in tumor volume and correlated with decreased XPO1 expression by immunohistochemistry. Conversely, doxorubicin reduced tumor size without affecting uptake, indicating preserved XPO1-associated signal. Together, these findings demonstrate that [18F]selinexor PET functions as a noninvasive imaging tool for evaluating the in vivo pharmacokinetics and pharmacodynamic behavior of selinexor, and capturing treatment-induced alterations in XPO1 engagement, although further structural optimization will be required prior to potential translation.