H₄picoopa─Robust Chelate for ²²⁵Ac/¹¹¹In Theranostics

Abstract

The nuclear decay characteristics of 225Ac (E α = 5–8 MeV, linear energy transfer (LET) = ∼100 keV/μm, t 1/2 = 9.92 days) are well recognized as advantageous for the treatment of primary and metastatic tumors; however, suitable chelation systems are required, which can accommodate this radiometal. Since 225Ac does not possess any suitable low-energy, high abundance γ-ray emissions for nuclear imaging, there is a clear need for the development of other companion radionuclides with similar coordination characteristics and comparable half-lives, which can be applied in diagnostics. H4picoopa was designed and executed as a high-denticity ligand for chelation of [225Ac]­Ac3+, and the complexation characteristics have been explored through nuclear magnetic resonance (NMR) spectroscopy, solution thermodynamic stability studies, and radiolabeling. The ligand shows highly favorable complexation with La3+ (pM = 17.6), Lu3+ (pM = 21.3), and In3+ (pM = 31.2) and demonstrates effective radiolabeling of both [225Ac]­Ac3+ and [111In]­In3+ ions achieving quantitative radiochemical conversions (RCCs) under mild conditions (RT, 10 min), accompanied by high serum stability (>97% radiochemical purity (RCP) over 6 days). A bifunctional analogue of H4picoopa was synthesized and conjugated to the Pip-Nle-CycMSHhex peptide for targeting of MC1R positive melanoma tumors. In vivo single-photon emission computed tomography (SPECT) and biodistribution studies of the 111In-radiolabeled bioconjugate in mice bearing B16-F10 tumors showed good radiotracer stability, although improved tumor targeting could not be achieved for imaging purposes. This work highlights H4picoopa as a very promising platform for application of [225Ac]­Ac3+ and [111In]­In3+ as a theranostic pair and allows great versatility for the incorporation of other directing vectors. The logical synthetic approach reported here for bifunctional H4picoopa, involving an azide-functionalized covalent linker and CuI-catalyzed alkyne-azide cycloaddition, allows for ease of optimization of bioconjugate pharmacokinetics and will be valuable for further radiopharmaceutical applications moving forward.

H3TPAN-Triazole-Bn-NH2: Tripicolinate Clicked-Bifunctional Chelate for [225Ac]/[111In] Theranostics

“…19−21 The Boc-protected azide linker (S4) was coupled to alkyne 2 efficiently under microwave reaction conditions (90 °C, 1 h) using CuSO 4 as catalyst and sodium ascorbate as an in situ reducing agent. Syntheses for compound S4 have been outlined previously 18 and are given in the Supporting Information. The click reaction was also attempted under standard conditions (ambient temperature), which gave comparable yields of triazole 3 although longer reaction times (24−36 h) were required for complete conversion.…”

“…Preparation of H 3 TPAN-triazole-Bn-NH 2 (4) proceeds through a linear synthesis starting from the 1,8-diamino-3,6-dioxaoctane (NOON) backbone, Scheme . First, synthesis of the tris -picolinate substituted backbone (1) was carried out using the same approach as described previously for bifunctional H 4 picoopa, via the direct alkylation of 1,8-diamino-3,6-dioxaoctane with three equivalent of the methyl (6-bromomethyl)­picolinate (S2) under mild conditions. Further, N -alkylation of secondary amine 1 with propargyl bromide proceeded cleanly under mild conditions to generate the protected alkyne-functionalized ligand (2) in high yields.…”

“…The alkyne functionalization was selected for ease of incorporation of different azide-containing bifunctional linkers using Cu I -catalyzed Huigens 1,3-diploar cycloaddition reactions (“click”), which generates a 1,4-disubstituted-1,2,3-triazole ring that can act a further pendent donor arm for metal-ion coordination. − The Boc-protected azide linker (S4) was coupled to alkyne 2 efficiently under microwave reaction conditions (90 °C, 1 h) using CuSO 4 as catalyst and sodium ascorbate as an in situ reducing agent. Syntheses for compound S4 have been outlined previously and are given in the Supporting Information. The click reaction was also attempted under standard conditions (ambient temperature), which gave comparable yields of triazole 3 although longer reaction times (24–36 h) were required for complete conversion.…”

“…These ligands have been explored for chelation of suitable imaging radionuclides, including [ 132/133 La]La 3+ and [ 131 Ba]Ba 2+ . 10,15−17 Recently, our group introduced H 4 picoopa�a large, multidentate chelator with a flexible ether-based backbone�which demonstrated promising characteristics for developing 225 Ac/ 111 In theranostics, 18 with notably high radiochemical conversions (RCCs) and molar activities achieved under mild conditions, and high serum stability. Several limitations were noted, including a long multistep, multicomponent synthesis required to prepare the bifunctional analogue, which may discourage further translation of this chelator.…”

“…Recently, our group introduced H 4 picoopaa large, multidentate chelator with a flexible ether-based backbonewhich demonstrated promising characteristics for developing 225 Ac/ 111 In theranostics, with notably high radiochemical conversions (RCCs) and molar activities achieved under mild conditions, and high serum stability. Several limitations were noted, including a long multistep, multicomponent synthesis required to prepare the bifunctional analogue, which may discourage further translation of this chelator.…”