1. Synthesis and Evaluation of Bifunctional [2.2.2]-Cryptands for Nuclear Medicine Applications
- Author
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Anthony W. McDonagh, Caterina F. Ramogida, Brooke McNeil, and Brian O. Patrick
- Subjects
Molecular Structure ,010405 organic chemistry ,Industry standard ,Cryptand ,Bridged Bicyclo Compounds, Heterocyclic ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,3. Good health ,Inorganic Chemistry ,chemistry.chemical_compound ,Tetrazine ,chemistry ,Isothiocyanate ,Humans ,DOTA ,Azide ,Nuclear Medicine ,Radiopharmaceuticals ,Physical and Theoretical Chemistry ,Bifunctional - Abstract
For the first time, synthesis of bifunctional [2.2.2]-cryptands (CRYPT) and demonstration of radiolabeling with lead(II) (Pb2+) isotopes are disclosed herein. The synthesis is convenient and high-yielding and gives access to three distinct bifunctional handles (azide (-N3), isothiocyanate (-NCS), and tetrazine (-Tz)) that can enable the construction of radioimmunoconjugates for targeted and pretargeted therapy. Proof-of-principle CRYPT radiolabeling was successful with lead-203 ([203Pb]Pb2+) and demonstrated complexation efficiency superior to that of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and efficiency comparable to that of the current industry standard TCMC (1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane). In vitro human serum stability assays demonstrated excellent [203Pb]Pb-CRYPT stability over 72 h (91.7 ± 0.56%; n = 3). [203Pb]Pb-CRYPT-radioimmunoconjugates were synthesized from the corresponding CRYPT-immunoconjugate or by conjugating [203Pb]Pb-Tz-CRYPT to transcyclooctene modified trastuzumab (TCO-trastuzumab) via the inverse electron-demand Diels-Alder (IEEDA) reaction. This investigation reveals the potential for CRYPT ligands to become new industry standards for therapeutic and diagnostic radiometals in radiopharmaceutical elaboration.
- Published
- 2021