Small Molecules as Vectors for Radiopharmaceutical Therapy

Radiopharmaceutical therapy (RPT) with small molecule-based agents is already a standard-of-care in multiple clinical scenarios, including patients with metastatic, castration-resistant prostate cancer whose tumors express prostate-specific membrane antigen (PSMA; [¹⁷⁷Lu]Lu-PSMA-617), and patients with metastatic or unresectable neuroblastoma, pheochromocytoma, or paraganglioma ([¹³¹I]MIBG). Numerous lines of inquiry continue to be pursued with small-molecule radiotherapeutics, with investigators exploring new indications, scaffolds, radionuclides, and combination therapies. The use agents bearing α-emitting radionuclides is of particular interest, as these may ultimately become the preferred approach to the RPT of prostate cancer assuming the right balance of efficacy and toxicity can be found. Response assessment criteria are also evolving due to the drive to identify patients that are responding to RPT and thereby optimize the use of such expensive and potentially toxic agents. New and emerging targets for small-molecule RPT are also being pursued, including fibroblast-activating protein (FAP). The confluence of new scaffolds, new radionuclides, new targets, improved response-assessment algorithms, and new applications for artificial intelligence portends a bright future for small molecule-based RPT.