@article {Klingler1010, author = {Maximilian Klingler and Dominik Summer and Christine Rangger and Roland Haubner and Julie Foster and Jane Sosabowski and Clemens Decristoforo and Irene Virgolini and Elisabeth von Guggenberg}, title = {DOTA-MGS5, a New Cholecystokinin-2 Receptor-Targeting Peptide Analog with an Optimized Targeting Profile for Theranostic Use}, volume = {60}, number = {7}, pages = {1010--1016}, year = {2019}, doi = {10.2967/jnumed.118.221283}, publisher = {Society of Nuclear Medicine}, abstract = {Molecular imaging and targeted radiotherapy with radiolabeled cholecystokinin-2 receptor (CCK2R) targeting peptide probes holds high promise to improve the clinical management of patients with metastatic medullary thyroid carcinoma and other CCK2R-expressing malignancies. Low stability and suboptimal targeting of currently available radiolabeled peptide analogs has prompted us to seek new stabilization strategies. In this study, we present a new minigastrin analog with site-specific C-terminal modifications showing a highly optimized targeting profile. Methods: DOTA-D-Glu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-Nal-NH2 (DOTA-MGS5) radiolabeled with 111In, 68Ga, and 177Lu was evaluated in extensive in vitro stability studies. For 177Lu-DOTA-MGS5, additional metabolic studies were performed on BALB/c mice. Receptor affinity and cell uptake were studied in A431 human epidermoid carcinoma cells transfected with human CCK2R (A431-CCK2R), as well as the same cell line transfected with the empty vector (A431-mock). A431-CCK2R/A431-mock xenografted athymic BALB/c nude mice were used for biodistribution studies and small-animal SPECT/CT. Results: DOTA-MGS5 radiolabeled with 111In and 177Lu showed a highly increased stability against enzymatic degradation in different media up to 24 h of incubation. Similar results were observed for 68Ga-DOTA-MGS5 incubated up to 4 h. In the blood of mice injected with 177Lu-DOTA-MGS5, at least 70\% intact radiopeptide was detected up to 1 h after injection. The unlabeled peptide and the complexes with the natural isotopes showed retained receptor affinity, and the radiopeptides showed unexpectedly high cell uptake in A431-CCK2R cells (\>60\% at 4 h). Regardless of the radiometal used for labeling, impressively high uptake in A431-CCK2R xenografts was found (\~{}20\% injected activity/g 1{\textendash}4 h after injection), whereas the uptake in A431-mock xenografts was negligible. Low background activity and favorable tumor-to-kidney ratios (4{\textendash}6) allowed for high image contrast in small-animal SPECT/CT. Conclusion: The excellent targeting properties of DOTA-MGS5 support future clinical studies evaluating the diagnostic and therapeutic potential in patients with progressive or metastatic medullary thyroid carcinoma, as well as other advanced-stage CCK2R-expressing malignancies.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/60/7/1010}, eprint = {https://jnm.snmjournals.org/content/60/7/1010.full.pdf}, journal = {Journal of Nuclear Medicine} }