@article {doi:10.1021/acs.bioconjchem.2c00364,
	title = {H4picoopa-Robust Chelate for 225Ac/111In Theranostics},
	journal = {Bioconjugate Chem.},
	volume = {33},
	number = {10},
	year = {2022},
	note = {PMID: 36126334},
	month = {09/2022},
	pages = {1900-1921},
	abstract = {<p>The nuclear decay characteristics of 225Ac (Eα = 5\&ndash;8 MeV, linear energy transfer (LET) = \&sim;100 keV/μm, t1/2 = 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 (\&gt;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.</p>},
	doi = {10.1021/acs.bioconjchem.2c00364},
	url = {https://doi.org/10.1021/acs.bioconjchem.2c00364},
	author = {Wharton, Luke and Jaraquemada-Pelaez, Maria de Guadalupe and Zhang, Chengcheng and Zeisler, Jutta and Rodr{\'\i}guez-Rodr{\'\i}guez, Cristina and Osooly, Maryam and Radchenko, Valery and Yang, Hua and Lin, Kuo-Shyan and B{\'e}nard, Francois and Schaffer, Paul and Orvig, Chris}
}
