Chelation strategies for s-, p-, and f-block radionuclides for targeted alpha therapy

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PROJECT SUMMARY Targeted alpha therapy (TAT) employs alpha-emitting radionuclides in conjunction with biological targeting vectors to destroy tumor cells. Alpha particles are extremely potent due to their high linear energy transfer, rendering these types of radioactive emissions highly promising for the eradication of cancer cells. The efficacy of alpha particle therapy is evidenced by the recent FDA approval of the alpha emitter 223RaCl2 for the treatment of prostate cancer patients with bone metastases. Because 223RaCl2 is a non-targeted form of TAT, however, it cannot be used in its current form to treat soft tissue tumors or visceral metastases. In order to treat these forms of cancer, alpha-emitting radionuclides need to be conjugated to biological targeting vectors, such as antibodies and peptides, that bind with high specificity and affinity to receptors that are selectively overexpressed in cancer cells. A key challenge for the design of such targeted constructs lies in the need for a bifunctional chelating agent, a ligand that is covalently bound to the targeting vector and that forms exceedingly stable complexes with the alpha-emitting radiometals in vivo. The bifunctional chelator acts as the requisite attachment between the alpha emitter and targeting vector, fundamentally enabling the concept of targeted TAT. The development of effective bifunctional chelators for radionuclides that are useful for TAT, however, has been hindered by the poorly established coordination chemistry of these metal ions. In this project, we will study the coordination chemistry of and design new ligands for metal ions that are valuable for TAT. These fundamental chelation studies will drive future efforts to design new bifunctional chelating agents, enabling the use of targeted TAT in the clinic. Our efforts will focus on three metal ions, spanning the s-, p-, and f-block of the periodic table. In Specific Aim 1, we will probe the coordination chemistry of Ra2+ and design new chelators that can stably retain this ion. We will pursue large macrocycles that are conformationally constrained as potential ligands for this ion. These efforts will facilitate the implementation of the FDA-approved alpha-emitter 223Ra for use in soft tissue or visceral metastases. Specific Aim 2 will focus on the p-block ion Bi3+. The radionuclide 213Bi is a short-lived alpha- emitter that has been evaluated in clinical trials. Our design strategies for this ion will rely on its high affinity for nitrogen donor atoms and the anisotropic coordination sphere resulting from its stereoactive 6s2 lone pair. In Specific Aim 3, chelation approaches for 230U will be developed. This radionuclide has ideal properties for use in TAT but has not yet been used for this application. Our efforts to develop ligands for the UO22+ ion, the most stable form of this element in aqueous solution, will enable its therapeutic implementation. We will design ligands that bind in the equatorial plane of the UO22+ cation and provide outer-sphere hydrogen bond donors for interacting with the terminal oxo ligands. Collectively, the fundamental coordination chemistry in this project will render these alpha-emitting radionuclides accessible for therapeutic applications.