Chelator Free Radiolabeling and Preclinical Evaluation of η 6 ‐Arene Sandwich Complexes of Lenalidomide With Rhenium and Technetium‐99m

Lenalidomide is a clinically important immunomodulatory drug that exerts activity through binding to the intracellular protein cereblon (CRBN). Despite its widespread therapeutic use, radiolabeling strategies that could enable investigation of lenalidomide pharmacokinetics or support the development of metallodrug analogs have not been reported. We report the synthesis and characterization of sandwich complexes [M(η 6 ‐lena) 2 ] + (M =  99m Tc or Re), establishing a bioorganometallic platform for direct, chelator‐free radiolabeling of lenalidomide. [ 99m Tc(η 6 ‐lena) 2 ] + was synthesized in aqueous media from [ 99m TcO 4 ] − , while the rhenium analog, [Re(η 6 ‐lena) 2 ] + , enabled structural and biochemical characterization. A monoligand complex, [Re(η 6 ‐C 6 H 6 )(η 6 ‐lena)] + , was synthesized to probe structure–activity relationships, revealing further reduced CRBN binding relative to the bis–ligand complex, [Re(η 6 ‐lena) 2 ] + . While [Re(η 6 ‐lena) 2 ] + retains measurable binding to CRBN (IC 50  = 43.8 µM) compared to the parent ligand, lenalidomide (IC 50  = 7.6 µM). Biodistribution of [ 99m Tc(η 6 ‐lena) 2 ] + in healthy mice demonstrated rapid blood clearance and predominant renal excretion. These results demonstrate the feasibility of direct radiolabeling of lenalidomide and provide insight into the effects of bioorganometallic modification on CRBN interaction and in vivo pharmacokinetics.