The Advancement of Targeted Alpha Therapy and the Role of Click Chemistry Therein

Abstract

Recent years have seen a swift rise in the use of α-emitting radionuclides such as ²²⁵Ac and ²²³Ra as various radiopharmaceuticals to treat (micro)metastasized tumors. They have shown remarkable effectiveness in clinical practice owing to the highly cytotoxic α-particles that are emitted, which have a very short range in tissue, causing mainly double-stranded DNA breaks. However, it is essential that both chelation and targeting strategies are optimized for their successful translation to clinical application, as α-emitting radionuclides have distinctly different features compared to β^--emitters, including their much larger atomic radius. Furthermore, upon α-decay, any daughter nuclide irrevocably breaks free from the targeting molecule, known as the recoil effect, dictating the need for faster targeting to prevent healthy tissue toxicity. In this review we provide a brief overview of the current status of targeted α-therapy and highlight innovations in α-emitter-based chelator design, focusing on the role of click chemistry to allow for fast complexation to biomolecules at mild labeling conditions. Finally, an outlook is provided on different targeting strategies and the role that pre-targeting can play in targeted alpha therapy.

Keywords: chelators; click chemistry; complexation; pre-targeting; radionuclides; recoiling daughters; targeted alpha therapy; targeting vectors; tumors.

Figure 1

Characteristics of the main α-emitting radionuclides of medical interest, including their respective half-lives (blue) and main alpha energy (red), based on nuclear data from Live Chart of Nuclides [20]: (a) ¹⁴⁹Tb [21], (b) ²¹¹At [22], (c) ²²⁵Ac and ²¹³Bi [23,24,25], (d) ²²⁴Ra and ²¹²Bi [26], and (e) ²²⁷Th and ²²³Ra [23,27].

Figure 3

Chemical structures of selected chelators (a) and thermodynamic formation stability constants (logK_ML) measured after complexation with the various Ln³⁺ ions plotted vs. ionic radii (b,c), adopted from [58].

Figure 6

(a) Schematic representation of two administration routes for radiopharmaceuticals: direct administration of radioligands (left) and two–step administration of chemically modified targeting vectors (e.g., antibodies), followed by radioligands provided with matching functional groups designed for a click reaction (right); (b) radiopharmaceuticals involved in the corresponding study [75].

Figure 2

Structures of the bifunctional chelators considered for clinical applications in combination with α-emitters.

Scheme 1

Two-step and one-step labeling protocols for ²²⁵Ac antibody derivatives. Adapted from [60,62].

Scheme 2

Click reaction proposed for radiolabeling of a TCO-functionalized antibody with [²²⁵Ac]Ac–DOTA–Tz [63].

Figure 4

An example of a modular assembly of radiopharmaceuticals: (a) schematic representation of a one–pot copper-catalyzed click reaction, (b) the radiochemical yield as a function of reaction time, (c) comparison of radiochemical yields (10 min, 60 °C) of compounds composed of azido derivatives (yellow circle) and alkyne moieties (green circle): 1–4 = A + R₁–R₄; 5–6 = B + R₁–R₄; and 7–12 = C + R₁–R₄. Adopted from [64].

Figure 5

Chelators pre-functionalized for bioconjugation with α-emitting radiocomplexes with tumor-targeting vectors.