Coordination Chemistry of [Y(pypa)]- and Comparison Immuno-PET Imaging of [44Sc]Sc- and [86Y]Y-pypa-phenyl-TRC105

Both scandium-44 and yttrium-86 are popular PET isotopes with appropriate half-lives for immuno-positron emission tomography (immuno-PET) imaging. Herein{,} a new bifunctional H4pypa ligand{,} H4pypa-phenyl-NCS{,} is synthesized{,} conjugated to a monoclonal antibody{,} TRC105{,} and labeled with both radionuclides to investigate the long-term in vivo stability of each complex. While the 44Sc-labeled radiotracer exhibited promising pharmacokinetics and stability in 4T1-xenograft mice (n=3) even upon prolonged interactions with blood serum proteins{,} the progressive bone uptake of the 86Y-counterpart indicated in vivo demetallation{,} obviating H4pypa as a suitable chelator for Y3+ ion in vivo. The solution chemistry of [natY(pypa)]- was studied in detail and the complex found to be thermodynamically stable in solution with a pM value 22.0{,} ≥3 units higher than those of the analogous DOTA- and CHX-A”-DTPA-complexes; the 86Y-result in vivo was therefore most unexpected. To explore further this in vivo lability{,} Density Functional Theory (DFT) calculation was performed to predict the geometry of [Y(pypa)] and the results were compared with those for the analogous Sc- and Lu-complexes; all three adopted the same coordination geometry (i.e. distorted capped square antiprism){,} but the metal-ligand bonds were much longer in [Y(pypa)] than in [Lu(pypa)] and [Sc(pypa)] {,} which could indicate that the size of the binding cavity is too small for the Y3+ ion{,} but suitable for both the Lu3+ and Sc3+ ions. Considered along with results from [86Y][Y(pypa-phenyl-TRC105)]{,} it is noted that when matching chelators with radionuclides{,} chemical data such as the thermodynamic stability and in vitro inertness{,} albeit useful and necessary{,} do not always translate to in vivo inertness{,} especially with the prolonged blood circulation of the radiotracer bound to a monoclonal antibody. Although H4pypa is a nonadentate chelator{,} which theoretically matches the coordination number of the Y3+ ion{,} we show herein that its binding cavity{,} in fact{,} favors smaller metal ions such as Sc3+ and Lu3+ and further exploitation of the Sc-pypa combination is desired.