H4picoopaRobust Chelate for 225Ac/111In Theranostics

• Published in: Bioconjugate chemistry Vol. 33; no. 10; pp. 1900 - 1921
• Main Authors: Wharton, Luke, Jaraquemada-Peláez, María de Guadalupe, Zhang, Chengcheng, Zeisler, Jutta, Rodríguez-Rodríguez, Cristina, Osooly, Maryam, Radchenko, Valery, Yang, Hua, Lin, Kuo-Shyan, Bénard, François, Schaffer, Paul, Orvig, Chris
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.10.2022; Amer Chemical Soc
• Subjects: Alkynes; Biochemical Research Methods; Biochemistry & Molecular Biology; Chelation; Chemistry; Chemistry, Multidisciplinary; Chemistry, Organic; Complexation; Computed tomography; Cycloaddition; Emission analysis; Emissions; Energy transfer; Gamma emission; In vivo methods and tests; Life Sciences & Biomedicine; Ligands; Linear energy transfer (LET); Medical imaging; Melanoma; Metastases; NMR; NMR spectroscopy; Nuclear magnetic resonance; Optimization; Pharmaceuticals; Pharmacokinetics; Photon emission; Physical Sciences; Precision medicine; Radioactive tracers; Radiochemistry; Radioisotopes; Radiolabelling; Science & Technology; Single photon emission computed tomography; Spectroscopy; Stability; Tumors; EQUILIBRIUM-CONSTANTS; MELANOCYTE-STIMULATING HORMONE; STABILITY; MELANOCORTIN-1 RECEPTOR; IN-111; LIGAND; HOCTAPA; DERIVATIVES; RELEVANT
• ISSN: 1043-1802; 1520-4812; 1520-4812
• DOI: 10.1021/acs.bioconjchem.2c00364

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.