Open AccessPolyazamacrocycle Ligands Facilitate 89Zr Radiochemistry and Yield 89Zr Complexes with Remarkable Stability
Author(s) -
Darpan N. Pandya,
Kelly E. Henry,
Cynthia S. Day,
Stephen A. Graves,
Veronica L. Nagle,
Thomas R. Dilling,
Akesh Sinha,
Brandie M. Ehrmann,
Nikunj Bhatt,
Yusuf Menda,
Jason S. Lewis,
Thaddeus J. Wadas
Publication year - 2020
Publication title -
inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.348
H-Index - 233
eISSN - 1520-510X
pISSN - 0020-1669
DOI - 10.1021/acs.inorgchem.0c02722
Subject(s) - zirconium , chemistry , yield (engineering) , reactivity (psychology) , characterization (materials science) , nuclear chemistry , radiochemistry , nanotechnology , inorganic chemistry , materials science , medicine , alternative medicine , pathology , metallurgy
Over the last three decades, the chemistry of zirconium has facilitated antibody development and the clinical management of disease in the precision medicine era. Scientists have harnessed its reactivity, coordination chemistry, and nuclear chemistry to develop antibody-based radiopharmaceuticals incorporating zirconium-89 ( 89 Zr: t 1/2 = 78.4 h, β + : 22.8%, E β+max = 901 keV; EC: 77%, E γ = 909 keV) to improve disease detection, identify patients for individualized therapeutic interventions. and monitor their response to those interventions. However, release of the 89 Zr 4+ ion from the radiopharmaceutical remains a concern, since it may confound the interpretation of clinical imaging data, negatively affect dosimetric calculations, and hinder treatment planning. In this report, we relate our novel observations involving the use of polyazamacrocycles as zirconium-89 chelators. We describe the synthesis and complete characterization of zirconium 2,2',2″,2‴-(1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetrayl)tetraacetic acid (Zr-TRITA), zirconium 3,6,9,15-Tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (Zr-PCTA), and zirconium 2,2',2″-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (Zr-NOTA). In addition, we elucidate the solid-state structure of each complex using single-crystal X-ray diffraction analysis. Finally, we found that [ 89 Zr]Zr-PCTA and [ 89 Zr]Zr-NOTA demonstrate excellent stability in vitro and in vivo and provide a rationale for these observations. These innovative findings have the potential to guide the development of safer and more robust immuno-PET agents to improve precision medicine applications.