Design, Synthesis, and Biological Evaluation of 99m Tc‐Labeled Thalidomide Analogs as Novel Tumor‐Targeting Radiopharmaceuticals

ABSTRACT This study aimed to develop tumor‐selective radiopharmaceuticals for noninvasive imaging using three thalidomide analogs: N‐(2,6‐dioxopiperidin‐3‐yl)‐2‐((3‐ethyl‐7‐nitro‐4‐oxo‐3,4‐dihydroquinazolin‐2‐yl)thio)acetamide (DPDQA), 2‐amino‐N‐(2,6‐dioxopiperidin‐3‐yl)benzamide (ADPB), and 2‐(2‐chloroquinazolin‐4‐yl)hydrazine‐1‐carboxamide (CQHC). These compounds were radiolabeled with 99m Tc via a direct labeling method using sodium dithionite (Na 2 S 2 O 4 ) as a reducing agent. Optimal labeling conditions were determined by evaluating pH, ligand/reducing agent amounts, reaction time, and temperature. Radiochemical purity reached 92% ± 0.31% for 99m Tc‐DPDQA (pH 8, 500‐μg ligand, 500‐mg Na 2 S 2 O 4 , 15 min), 89.8% ± 0.128% for 99m Tc‐ADPB (pH 7, 800‐μg ligand, 25‐mg Na 2 S 2 O 4 , 15 min), and 92% ± 0.16% for 99m Tc‐CQHC (pH 10, 200‐μg ligand, 150‐mg Na 2 S 2 O 4 , 30 min). All complexes demonstrated good in vitro stability up to 24 h. In vivo biodistribution studies in tumor‐bearing mice revealed high tumor uptake ( T / NT ratios: 19.75, 6.18, and 22.72 for 99m Tc‐DPDQA, 99m Tc‐ADPB, and 99m Tc‐CQHC, respectively), with renal excretion as the primary clearance pathway. These results highlight the potential of 99m Tc‐labeled thalidomide analogs as selective tumor‐imaging agents outperforming existing agents like 99m Tc‐TEPA.