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.