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Non-macrocyclic chelators for metal-based radiopharmaceuticals Choudhary, Neha

Abstract

Radiometals have unique decay properties and half-lives. In order to harness their valuable properties for use in medicine, we need chelators to tightly bind them and transport them to the desired site in vivo for imaging or therapy. The macrocyclic chelators used in the clinic suffer from poor metal coordination match and exhibit slower kinetics, while the non-macrocyclic chelators are known for their faster complexation times under ambient conditions and are compatible for conjugation to antibodies for specific targeting. This thesis describes the design, synthesis and evaluation of non-macrocyclic chelators for radiometals. The coordination chemistry of metal complexes has been studied by solid-state crystal structure analysis, NMR spectroscopy, combined potentiometric and UV-Vis spectrophotometric titrations, and DFT calculations to study their aqueous chemistry. Radiolabeling studies and transchelation studies against human serum proteins were conducted to evaluate their use in radiopharmaceuticals. Bispidine-based H₂bixpox² was synthesized and the metal complexes with In³⁺ and Lu³⁺ were characterized by X-ray single-crystal structure and NMR spectroscopy. Radiolabeling experiments revealed high radiolabeling efficacy of H₂bispox² with [¹¹¹In]In³⁺ and [¹⁷⁷Lu]Lu³⁺. H₃glyox, a hexadentate chelator was synthesized and was found to form thermodynamically stable neutral complexes with three major radiometal ions ([⁴⁴Sc]Sc³⁺, [⁶⁸Ga]Ga³⁺ and [¹¹¹In]In³⁺); the pM values follow the order: pIn (34.0) > pSc (26.0) > pCu (25.2) > pGa (24.9) > pLu (18.1) > pMn (12.0). Quantitative radiolabeling with [⁶⁸Ga]Ga³⁺ (RCY > 95%, [L] = 10-5 M) and [¹¹¹In]In³⁺ (RCY > 99%, [L] = 10⁻⁸ M) was achieved under ambient conditions (RT, pH 7 and 15 min) with very high apparent molar activities of 750 MBq/μmol and 650 MBq/nmol, respectively. The chelation enhanced fluorescence of the natSc(glyox) and natGa(glyox) complexes was used to investigate their cellular distribution in the live HeLa cells. Preliminary studies were done to access the use of [Mn(glyox)]⁻ complex for 52/55Mn-based bimodal PET/MRI imaging and the results were promising. Lastly, a preorganized octadentate chelator, H₄HBEDpa was designed and synthesized, which forms highly thermodynamically stable complexes with trivalent metal ions. Competition experiments against excess apo-transferrin revealed high resistance of the [Fe(HBEDpa)]⁻ complex (logKFeL = 36.62) to transchelation even after 7 days.

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