How should chelating agents be selected for targeted radionuclides?

Chelating agents in targeted radionuclides serve as the "key connectors" that enable precise delivery of radionuclides to tumor cells. These agents must securely bind the radionuclide (ensuring high stability within the body) and be capable of conjugating to targeting molecules (dual functionality).

Overview of Classical and Novel Chelating Agents

1.Macrocyclic chelating agents

These chelating agents possess a cyclic structure and form highly stable complexes upon complexation.

· Representative members: DOTA and its derivatives (e.g., NODA-GA)

· Applicable radionuclides: ¹⁷⁷Lu, ⁹⁰Y, ⁶⁸Ga, ¹¹¹In, ²²⁵Ac, etc.

· Examples of marketed drugs: Lutathera (¹⁷⁷Lu-DOTATATE, for the treatment of neuroendocrine tumors), Pluvicto (¹⁷⁷Lu-PSMA-617, for the treatment of prostate cancer).

· Key features and challenges: DOTA exhibits exceptionally high thermodynamic and kinetic stability, making it the most widely used "gold standard" in clinical applications. However, for α-emitting radionuclides with large ion radii, such as ²²⁵Ac, the chelation capability of conventional DOTA faces significant challenges.

2. Linear/non-big-lag chelating agents

The structure is an open chain; typically, the labeling conditions are milder and faster.

· Representative members: DTPA and its derivatives (e.g., DTPA-NCS), HBED-CC (specifically for Ga)

· Applicable radionuclides: ⁹⁰Y (DTPA), ⁶⁸Ga (HBED-CC)

· Examples of marketed drugs: Zevalin (⁹⁰Y-Tositumomab, using DTPA-NCS, for the treatment of lymphoma).

·Key features and challenges: Labeling is straightforward and rapid; however, its stability is generally inferior to that of macrocyclic compounds, and the current applications of HBED-CC are primarily limited to gallium radionuclides.

3. Novel chelating agents for large-sized radionuclides

Designed to address the stabilization of chelation for heavy-ion radionuclides (e.g.²²⁵Ac) with large ionic radii.

· Representative members: Macropa and its derivatives (e.g., macrodipa, py-macrodipa).

· Applicable radionuclides: ²²⁵Ac, ²¹³Bi, ²²³Ra, ¹³⁵La, etc.

· Research stage/clinical progress: Multiple Macropa-based ²²⁵Ac drugs have entered clinical trials.

· Key features and challenges: It exhibits "reverse size selectivity," meaning it is more stable when chelating large metal ions; this property positions it at the forefront of α-radioisotope therapy research.

The selection of chelating agents is not arbitrary; it is primarily based on the following scientific principles.

· Dimensional matching and selectivity: This is the foremost principle. Since there are significant differences in ion radii among different radionuclides, it is essential to select an appropriate cavity that can "encapsulate" them. For example, DOTA performs well with small-and medium-sized radii of ¹⁷⁷Lu, whereas Macropa is specifically designed to "fit" the large radius of ²²⁵Ac.

· Dual functionality: An ideal chelator possesses one end capable of firmly binding to metals and the other end (e.g., the NCS group) capable of covalently linking targeting molecules (e.g., antibodies or peptides), thereby forming a tripartite drug system consisting of "target moiety – chelator – radionuclide."

· In vivo stability: This is the lifeline of safety. A stable complex can prevent the radioactive nuclide from detaching within the body, thereby avoiding radiation-induced damage to normal tissues (particularly the bone marrow and kidneys). Stability is typically quantified using the "stability constant (log K);" the higher the value, the more stable the compound.

Cutting-edge Research Directions

1. "Dual-size selective" chelating agents—such as Py-Macrodipa—can simultaneously and efficiently chelate radionuclides with significantly different sizes (e.g., ¹³⁵La and ⁴⁴Sc), thereby providing a novel tool for achieving "integrated diagnosis and therapy" (utilizing a single carrier for both diagnostic imaging and therapeutic purposes).

2. Development of new ligand scaffolds: Researchers are continuously modifying scaffolds such as Macropa or developing novel chelators like G-macropa to optimize performance or enable other functions, such as radionuclide separation.

The selection of chelating agents for targeted radionuclides is a precise matching science; its core objective is to achieve the optimal balance among the radionuclide, the chelating agent, and the targeting molecule, thereby ensuring both the stability of the drug in vivo and its therapeutic efficacy.