p-NO₂–Bn–H₄neunpa and H₄neunpa–Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and ¹¹¹In Immuno-Single Photon Emission Computed Tomography Imaging

Abstract

Potentially nonadentate (NO) bifunctional chelator p-SCN-Bn-Hneunpa and its immunoconjugate Hneunpa-trastuzumab for In radiolabeling are synthesized. The ability of p-SCN-Bn-Hneunpa and Hneunpa-trastuzumab to quantitatively radiolabel InCl at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In, Bi, and La resulted in high conditional stability constant (pM) values. In vitro human serum stability assays have demonstrated both In complexes to have high stability over 5 days. Mouse biodistribution of [In][In(p-NO-Bn-neunpa)], compared to that of [In][In(p-NH-Bn-CHX-A″-diethylenetriamine pentaacetic acid (DTPA))], at 1, 4, and 24 h shows fast clearance of both complexes from the mice within 24 h. In a second mouse biodistribution study, the immunoconjugates In-neunpa-trastuzumab andIn-CHX-A″-DTPA-trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of In-neunpa-trastuzumab compared to that ofIn-CHX-A″-DTPA-trastuzumab. These results were also confirmed by immuno-single photon emission computed tomography (immuno-SPECT) imaging in vivo. These initial investigations reveal the acyclic bifunctional chelator p-SCN-Bn-Hneunpa to be a promising chelator for In (and other radiometals) with high in vitro stability and also show Hneunpa-trastuzumab to be an excellent In chelator with promising biodistribution in mice.

Thorium chelators for targeted alpha therapy: Rapid chelation of thorium‐226

“…Chelation of 227 Th using the nonadentate ligands 4 and 5 resulted in no or low yields. Although it was reported that 111 In-labeled 4, H 4 neunpa-p-Bn-NO 2 , has exceptional stability, 31 the extended diethylenetriamine backbone and the nonadentate N 5 O 4 coordination motif does not seem to be suitable for coordinating the thorium ion. Attempts at chelation of 227 Th with ligand 5, H 4 pypa, resulted in low labeling yields with multiple radioactive peaks, including one large peak observed from t R = 11 min to t R = 20 min.…”

“…Ligands containing the pa moieties, 3-6, were prepared as previously published. 28,[31][32][33][34][35]…”

Bismuth-213 for Targeted Radionuclide Therapy: From Atom to Bedside

“…The patient was treated with two cycles of 213 Bi-PSMA-617 with a cumulative activity of 592 MBq. Restaging with 68 Ga-PSMA PET/CT after 11 months showed an outstanding molecular imaging response. This patient also exhibited a biochemical response (decrease in prostate-specific antigen levels from 237 µg/L to 43 µg/L) [80].…”

“…CAFs, in contrast with normal fibroblasts, overexpress fibroblast activation protein α (FAP). Novel radioprobes, both for diagnostic and therapeutic applications, were designed and are based on FAP inhibitors (FAPI) as vector molecule (e.g., 68 Ga-DOTA-FAPI-46). FAPI PET images are characterized by rapid kinetics, very low background activity (no uptake in brain, muscle, brown fat, bowel, etc.)…”

“…A study has demonstrated that derivatives of [ 68 Ga]Ga-DOTA-AmBz-MVK-OH could be cleaved specifically by neutral endopeptidase (NEP), and therefore the amino acids linker MVK could reduce kidney uptake of radiolabeled DOTA-conjugated peptides and peptidomimetics [125]. These findings would allow development of radiometal-based radiopharmaceuticals with clinically relevant lower renal radioactivity levels [126].…”