RT Journal Article
SR Electronic
T1 DOTA-MGS5, a New Cholecystokinin-2 Receptor-Targeting Peptide Analog with an Optimized Targeting Profile for Theranostic Use
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1010
OP 1016
DO 10.2967/jnumed.118.221283
VO 60
IS 7
A1 Maximilian Klingler
A1 Dominik Summer
A1 Christine Rangger
A1 Roland Haubner
A1 Julie Foster
A1 Jane Sosabowski
A1 Clemens Decristoforo
A1 Irene Virgolini
A1 Elisabeth von Guggenberg
YR 2019
UL http://jnm.snmjournals.org/content/60/7/1010.abstract
AB 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 1–4 h after injection), whereas the uptake in A431-mock xenografts was negligible. Low background activity and favorable tumor-to-kidney ratios (4–6) 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.