Abstract

Theranostics—integrating diagnostic imaging and targeted radionuclide therapy on a shared molecular platform—is driving a fundamental transformation in nuclear medicine practice. This review systematically examines drug interactions that directly alter biodistribution, target expression and dosimetry in preclinical theranostic research, yet are rarely incorporated into standard development protocols. Four mechanistic categories are considered: pharmacokinetic, pharmacodynamic, radiosensitivity modification, and toxic interactions. Among clinically approved theranostic radioligands, prostate-specific membrane antigen (PSMA)-targeted agents are subject to marked modulation by androgen deprivation therapy and androgen-receptor pathway inhibitors, which upregulate PSMA expression up to eightfold, while taxane chemotherapy suppresses the same target—findings that directly govern optimal radioligand timing. In peptide receptor radionuclide therapy, competitive receptor inhibition by cold somatostatin analogues mandates a defined washout period before treatment, while combination with polyadenosine-diphosphate-ribose polymerase inhibitors amplifies deoxyribonucleic acid double-strand break accumulation and produces clinically relevant radiosensitivity synergy. Fibroblast activation protein-targeted radioligands interact synergistically with immune checkpoint inhibitors through tumour microenvironment remodeling, evidenced by increased tumour-infiltrating lymphocytes and programmed death ligand-1 upregulation in preclinical models. With CXC chemokine receptor type 4-targeted radioligands, direct receptor competition from plerixafor and the expression-altering effects of hematological agents (ibrutinib, granulocyte colony-stimulating factor) constitute distinct interaction categories. Radioligand-specific priorities include daughter-nuclide redistribution and combined toxicity for alpha emitters, copper-chelator transporter competition for ⁶⁴Cu-based radiopharmaceuticals, and in vivo deastatination with mandatory normal-tissue blocking for ²¹¹At. Anesthetic agent selection emerges as an underappreciated methodological variable that substantially affects biodistribution outcomes. Physiologically based pharmacokinetic modelling is increasingly central to the quantitative assessment and translational prediction of these interactions. Systematic evaluation of drug interactions in the preclinical phase will accelerate radiopharmaceutical development and strengthen the safety framework for future combination treatment regimens.