Inter- or intra-tumor heterogeneity refers to the genetic, epigenetic, and phenotypic variability that characterizes tumor cells. Regardless of its nature, this complexity represents a great challenge for diagnosis and treatment, since cells with different characteristics may respond differently to therapies, resulting in drug resistance and/or relapses. Furthermore, it has emerged that this heterogeneity can change over time or following a stimulus, such as a treatment. Molecular imaging is an essential tool in oncology. By enabling the identification of specific metabolic or receptor alterations of tumor cells, it provides a more accurate diagnosis, prognosis, and allows personalizing treatments. To date, addressing these challenges may be crucial for accurate diagnosis and therapeutic choice. In recent years, the design, synthesis, and characterization of bispecific radioligands (BRLs) with dual targeting capacity has emerged. In this review, we discuss the in vitro and in vivo studies of this new class of radiopharmaceuticals conducted so far, while assessing their potential advantages over traditional single-target radiopharmaceuticals.

Background/Objectives: Lutathera^® ([¹⁷⁷Lu]Lu-DOTA-TATE) is the first radiolabelled somatostatin (SST) analog approved for the treatment of patients with well-differentiated (G1 and G2) unresectable or metastatic gastro-entero-pancreatic neuro-endocrine-neoplasms (GEP-NENs). The bone marrow and kidneys are critical organs for RLT with [¹⁷⁷Lu]Lu-DOTA-TATE. Our purpose was to evaluate hematological and renal toxicity in 29 patients (18 males, 11 females) treated with Lutathera^®. Methods: According to standard protocols, four cycles of (¹⁷⁷Lu)Lu-DOTA-TATE were administered every eight/nine weeks. Patients received pre-medication with anti-emetic and anti-acid drugs and a slow amino acid infusion for renal protection. Blood count and serum creatinine data were collected at three time points: before the first cycle, after the second cycle, and at the end of treatment. Results: We found that almost all hematological parameters significantly decreased between the baseline and/or interim and post-therapy evaluation, although without a clinical impact. The presence of total tumor load or bone metastases had no influence on these findings, while male patients showed less hematological toxicity than females. Conversely, creatinine levels did not vary during treatment. Conclusions: Our study confirms that [¹⁷⁷Lu]Lu-DOTATATE RLT is safe and well tolerated despite some minor (grade 1) hematological toxicity.