Enhanced Targeting of Cholecystokinin-2 Receptor in MTC with ^177^Lu-DOTA-PP-F11N: The Role of Protease Inhibitors in Vivo Distribution

Metastatic medullary thyroid cancer (MTC) patients have few systemic treatment options, and radiolabeled gastrin analogs that target the cholecystokinin-2 receptor (CCK2R) could be a promising therapeutic strategy. However, their effectiveness is often reduced due to enzymatic degradation. This study investigates the performance of a chemically stabilized analog, 177Lu-DOTA-PP-F11N, compared to other analogs with different stabilities, and explores whether protease inhibitors can enhance CCK2R targeting.

The in vitro stability of the analogs was tested against various endoproteases, and their interaction with human MTC MZ-CRC-1 cells and A431-CCK2R(+) cells was evaluated. Biodistribution studies, both with and without the protease inhibitors phosphoramidon and thiorphan, were conducted in dual xenografts. Autoradiography and NanoSPECT/CT imaging were used to assess the biodistribution and uptake of 177Lu-DOTA-PP-F11N, and SPECT/CT images were acquired from a metastatic MTC patient.

Results indicated that 177Lu-DOTA-PP-F11N is less susceptible to neprilysins, a type of endoprotease, compared to other analogs. While intracellular cysteine proteases like cathepsin-L may play a role in degrading gastrin analogs, the uptake of all radiotracers was higher in MZ-CRC-1 tumors due to a higher number of binding sites. Notably, 177Lu-DOTA-PP-F11N showed almost double the uptake in MZ-CRC-1 tumors compared to 177Lu-DOTA-PP-F11. The coadministration of protease inhibitors significantly increased the uptake of 177Lu-DOTA-MG11 in CCK2R(+) tumors and the stomach, with a less pronounced effect on 177Lu-DOTA-PP-F11 and no significant influence on 177Lu-DOTA-PP-F11N.

Preliminary clinical data revealed high accumulation of 177Lu-DOTA-PP-F11N in tumors, stomach, kidneys, and colon. The study concludes that 177Lu-DOTA-PP-F11N performs as well as 177Lu-DOTA-MG11 without the need for protease inhibitors, suggesting that using single compounds without additives is preferable. The stomach, along with the kidneys, is highlighted as a potential dose-limiting organ in treatment.