Radionuclides

The choice of radionuclide is central to the design, function, and clinical success of radionuclide drug conjugates. Each radionuclide introduces specific physical and chemical characteristics, such as decay mode, half-life, and coordination chemistry, that determine whether it is suitable for imaging (diagnosis), therapy, or both (theranostics). Selecting the right radionuclide ensures controlled delivery, therapeutic potency, and compatibility with molecular targeting strategies.

Figure 2. Diagnostic and therapeutic roles of radionuclides in RDC theranostics.

RDC development primarily involves two major radionuclide categories:

1.     Diagnostic radionuclides

Diagnostic radionuclides emit β⁺ (positron) or γ (gamma) radiation, enabling PET or SPECT imaging to visualize biodistribution, receptor engagement, and tumor uptake.

·       Positron emitters (PET, β⁺)

These radionuclides are used for high-resolution molecular imaging. Examples include ⁶⁸Ga and ⁸⁹Zr. ⁶⁸Ga is widely used in peptide-based imaging agents and conveniently produced via a generator system. ⁸⁹Zr enables long-term PET tracking of antibodies and large biomolecules due to its extended half-life (78.4 h), which matches antibody pharmacokinetics.

·       Gamma emitters (SPECT, γ)

These radionuclides enable clinical SPECT imaging and dosimetry. ¹¹¹In and ⁶⁷Ga are classic SPECT nuclides used to evaluate RDC distribution. While ⁶⁷Ga also emits Auger electrons, its therapeutic relevance remains primarily experimental.

2.     Therapeutic radionuclides

Therapeutic radionuclides must emit particle radiation (β^- or α) capable of inducing lethal DNA damage within tumors. Ideal half-lives range from 6 hours to 10 days, balancing tumor uptake with acceptable radiation exposure.

·       Beta particle emitters (β^- therapy)

These nuclides provide cross-fire effects ideal for treating medium to large tumors. ¹⁷⁷Lu is the clinical gold standard in RDC therapy, with FDA-approved drugs such as Lutathera® and Pluvicto®. ⁹⁰Y delivers higher β energy and deeper tissue penetration, making it suitable for larger or less vascularized tumors.

·       Alpha particle emitters (α therapy)

Alpha emitters provide high linear energy transfer (LET) radiation, causing irreparable double-strand DNA breaks with minimal damage to surrounding tissue. ²²⁵Ac is a leading α emitter due to its strong cytotoxic potency and clinically compatible half-life (9.92 d), powering next-generation targeted alpha therapy.

·       Auger electron emitters

These radionuclides emit low-energy electrons with ultra-short path lengths (<1 μm), enabling subcellular precision when delivered to the nucleus. While radionuclides such as ¹⁹¹Pt are under investigation, their application in RDCs remains highly exploratory. 

Chelators

The chelator is specifically designed to handle radiometals (such as ¹⁷⁷Lu, ⁶⁸Ga, ⁸⁹Zr). Its function is to use multiple coordination bonds to tightly and stably sequester the metal ion, preventing demetallation in the complex physiological environment (i.e., the bloodstream), which is essential for minimizing off-target toxicity.

Chelators can be broadly categorized by their molecular structure:

·       Macrocyclic chelators

Macrocyclic chelators rely on rigid ring system that provide exceptional thermodynamic and kinetic stability – known as the macrocyclic effect. They are the clinical gold standards for modern therapeutic RDCs.

DOTA Family: DOTA and its derivatives (e.g., DOTAGA, DOTAM) are the preferred chelators for trivalent lanthanides, especially ¹⁷⁷Lu. Their robustness also supports theranostic pairing, as DOTA can coordinate ⁶⁸Ga for PET companion diagnostics.

NOTA Family: NOTA and its derivatives (e.g., NODAGA) exhibit ultrafast complexation kinetics ——and are widely used with ⁶⁸Ga and ⁶⁴Cu, making them ideal for short-lived PET imaging agents.

Sarcophagine (Sar) cage chelators: These chelators form three-dimensional cage structures with excellent kinetic inertness, offering outstanding stability for Cu radionuclides (⁶⁴Cu, ⁶⁷Cu).

Specialized macrocycles: DOTMP, a polyphosphonate macrocycle, is specifically engineered for bone-seeking radionuclides such as ¹⁶⁶Ho, enabling targeted skeletal irradiation. CB-DO2A represents a compact, constrained chelator designed to fine-tune coordination geometry and pharmacokinetics for selected radiometals.

Figure 3. Representative macrocyclic chelators used in RDCs.

 

·       Acyclic chelators

Acyclic chelators offer synthetic flexibility and rapid complexation, though generally with lower kinetic stability compared to macrocycles.

DFO: DFO is the established clinical chelator for ⁸⁹Zr, enabling long-term immunoPo-PET imaging.

HOPO: HOPO family, the next generation of DFO analogs, is being developed to improve in vivo stability.

DTPA: A versatile acyclic chelator commonly used for ¹¹¹In SPECT imaging agents and older ⁹⁰Y constructs.

TETA: TETA and its derivatives serve as open-chain copper chelators, historically used for ⁶⁴Cu labeling prior to widespread adoption of cage structures like sarcophagine.

HBED: HBED employs catecholate oxygen donors, offering exceptional affinity for hard metal ions such as ⁶⁸Ga.

MAG3 and N₂S₂: For ^99mTc, chelation is achieved via specialized donor systems such as MAG3 and N₂S₂, which exploit Tc’s unique coordination chemistry.

Trithiol chelator: The emerging trithiol chelator represents an opportunity for ¹⁹¹Pt, leveraging the strong affinity between Pt and sulfur for Auger electron therapy.

Figure 4. Representative acyclic chelators used in RDCs.

 

·       Covalent-radiolabeling (No chelator)

Halogen radionuclides, including ¹⁸F and ²¹¹At, are incorporated via direct covalent bonding, eliminating the need for metal chelators.

 

Linkers

The linker in an RDC functions as the bridge between the targeting ligand and the radionuclide payload. Though structurally small, it plays a critical role in determining in-vivo stability, pharmacokinetics, tissue penetration, clearance, and where radiation dose is finally deposited. Unlike ADC linkers, which usually carry cleavable motifs, RDC linkers are typically non-cleavable, designed to preserve radionuclide integrity from injection to decay.

Representative linker types used in RDCs

·       PEG chains or polyamide spacers – improve solubility and circulation

·       Aromatic linkers – maintain rigidity and control spatial orientation

·       Albumin-binding or lipid-modifying linkers – extend half-life in circulation

·       Bifunctional linkers – enable modular functionalization, such as dual labeling, fluorescent reporters, or multi-chelator platforms

Figure 5. Functional classification of non-cleavable linkers in RDCs.

 

The targeting ligand

The choice of targeting ligand is fundamental to the RDC concept, serving as the molecular guidance system that grants the entire construct specificity for cancer cells. This component must not only exhibit high affinity for its target but also maintain favorable pharmacokinetics that allow sufficient circulation time and tumor penetration.

Targeting ligands can be broadly classified by their structure.

·       Peptides

Short peptides offer rapid renal clearance and low off-target toxicity. They form the basis of major RDCs such as SSTR-targeting Lutathera® and FAP inhibitors that localize to the tumor microenvironment. Their fast kinetics make them ideal for diagnostic imaging with ⁶⁸Ga-labeled RDCs.

·       Small molecules

These ligands are engineered for optimal diffusion, enabling rapid tumor penetration and efficient systemic clearance. They are essential for compounds requiring blood-brain-barrier penetration and constitute the targeting backbone of PSMA-directed agents such as Pluvicto.

·       Antibodies

Full-length antibodies provide high target specificity and prolonged circulation, supporting robust tumor uptake in solid malignancies. They are typically paired with long-lived radionuclides such as ⁸⁹Zr (for PET imaging) or α-emitters for high-precision therapeutic dosing. To optimize pharmacokinetics, antibody fragments and nanobodies are increasing explored.

·       Nucleic acids

Aptamers and oligonucleotides offer programmable binding and exceptional stability. Though still in early research, they are being investigated as vectors for Auger electron emitters, aiming to deliver radiation directly to nuclear DNA for subcellular precision.

·       Nanoparticles

This emerging class includes liposomes, bacteria, and extracellular vesicles. These carriers exploit either passive accumulation via the Enhanced Permeability and Retention effect or active targeting mechanisms mediated by cellular recognition. They offer new opportunities to enhance RDC pharmacokinetics, overcome resistance, and enable multi-modal therapeutic strategies.

Figure 6. Comparison of targeting ligands in RDCs.

Supporting RDC development at Precise PEG

As outlined above, the performance of an RDC is ultimately governed by the rational integration of radionuclide selection, chelation chemistry, linker design, and targeting ligand optimization. While each component can be individually optimized, true clinical success requires a holistic, chemistry-driven approach that balances stability, pharmacokinetics, manufacturability, and biological performance.

At Precise PEG, we support RDC development with a portfolio of well-characterized chelators, linkers, and targeting ligands, and together with customizable chelator and linker architectures. (https://precisepeg.com/collections/radionuclide-drug-conjugates-rdcs) These capabilities enable our partners to efficiently translate RDC concepts into robust and scalable radiopharmaceutical solution.

 

Reference

1.     Tran, H. H.; Yamaguchi, A.; Manning, H. C. Radiotheranostic landscape: A review of clinical and preclinical development. Eur. J. Nucl. Med. Mol. Imaging 2025, 52, 2685. https://doi.org/10.1007/s00259-025-07103-7

2.     Roesch, F.; Martin, M. Radiometal-theranostics: the first 20 years. J. Radioanal. Nucl. Chem. 2023, 332, 1557. https://doi.org/10.1007/s10967-022-08624-3

3.     Yang, Y.; Wang, J.; Zhong, Y.; Tian, M.; Zhang, H. Advances in Radionuclide-Labeled Biological Carriers for Tumor Imaging and Treatment. ACS Appl. Mater. Interfaces 2025, 17, 4316. https://doi.org/10.1021/acsami.4c19059

4.     Zhang, S.; Wang, X.; Gao, X.; et al. Radiopharmaceuticals and their applications in medicine. Sig. Transduct. Target. Ther. 2025, 10, 1. https://doi.org/10.1038/s41392-024-02041-6