RT Journal Article
SR Electronic
T1 The Synthesis, Radiolabeling, and Characterization of 177Lu-Labeled Tetrazine Radioligands for Pretargeted Radioimmunotherapy
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1201
OP 1201
VO 57
IS supplement 2
A1 Membreno, Rosemery
A1 Houghton, Jacob
A1 Cook, Brendon
A1 Carnazza, Kathryn
A1 Lewis, Jason
A1 Zeglis, Brian
YR 2016
UL http://jnm.snmjournals.org/content/57/supplement_2/1201.abstract
AB 1201Objectives The synthesis, characterization, and optimization of 177Lu-labeled tetrazine-bearing radioligands for use in pretargeted radioimmunotherapy.Methods Current work in our group focuses on the pretargeted radiotherapy of pancreatic and colorectal cancer using the rapid and biorthogonal inverse electron demand Diels−Alder (IEDDA) reaction between tetrazine (Tz) and transcyclooctene (TCO). As part of an effort to develop a strategy for pretargeted radioimmunotherapy, Tz-PEG7-DOTA and Tz-PEG7-CHX-A˝-DTPA were synthesized modularly by standard chemical conjugation techniques. Structural characterizations were carried out by NMR and HRMS. Subsequently, 177Lu-Tz-PEG7-DOTA and 177Lu-Tz-PEG7-CHX-A”-DTPA were prepared via incubation of the ligand precursors with 177LuCl3 in ammonium acetate buffer. The stability of the radioligands was determined by agitation in PBS and human serum, followed by longitudinal analysis via instant thin layer chromatography (iTLC).Results Tz-PEG7-DOTA and Tz-PEG7-CHX-A”-DTPA were synthesized with overall yields of ~34% and ~86%, respectively. Radiolabeling of both ligands resulted in the isolation of 177Lu-Tz-PEG7-DOTA and 177Lu-Tz-PEG7-CHX-A”-DTPA in >98% radioisotopic purity and specific activities of 311 μCi/μg and 307 μCi/μg respectively. Stability studies reveal that 93.6 ± 0.9% of the 177Lu-Tz- PEG7-DOTA remains intact after 48 hours compared to 81.7 ± 5% of 177Lu-Tz-PEG7-CHX-A”-DTPA. Biodistribution studies in athymic nude mice bearing SW1222 xenografts show that 177Lu-Tz-PEG7-DOTA and huA33-TCO form an effective pair for the pretargeting of colorectal cancer.Conclusions We have successfully synthesized and radiolabeled Tz-PEG7-DOTA and Tz-PEG7-CHX-A"-DTPA for use in pretargeted radioimmunotherapy. 177Lu-Tz-PEG7-DOTA is an effective radioligand for in vivo pretargeting in a murine model of colorectal cancer. Pretargeted radiotherapy studies in murine models of colorectal and pancreatic cancer are forthcoming. $$graphic_B29CC900-A81E-45E2-A5DE-57B72BBD4FAD$$