Patients with metastatic medullary thyroid cancer (MTC) have limited systemic treatment options. The use of radiolabeled gastrin analogs targeting the cholecystokinin-2 receptor (CCK2R) is an attractive approach. However, their therapeutic efficacy is presumably decreased by their enzymatic degradation in vivo. We aimed to investigate whether the chemically stabilized analog ¹⁷⁷Lu-DOTA-PP-F11N (¹⁷⁷Lu-DOTA-(dGlu)₆-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH₂) performs better than reference analogs with varying in vivo stability, namely ¹⁷⁷Lu-DOTA-MG11 (¹⁷⁷Lu-DOTA-dGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH₂) and ¹⁷⁷Lu-DOTA-PP-F11 (¹⁷⁷Lu-DOTA-(dGlu)₆-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH₂), and whether the use of protease inhibitors further improves CCKR2 targeting. First human data on ¹⁷⁷Lu-DOTA-PP-F11N are also reported. Methods: In vitro stability of all analogs was assessed against a panel of extra- and intracellular endoproteases, whereas their in vitro evaluation was performed using the human MTC MZ-CRC-1 and the transfected A431-CCK2R(+) cell lines. Biodistribution without and with the protease inhibitors phosphoramidon and thiorphan was assessed 4 h after injection in MZ-CRC-1 and A431-CCK2R(+) dual xenografts. Autoradiography of ¹⁷⁷Lu-DOTA-PP-F11N (without and with phosphoramidon) and NanoSPECT/CT were performed. SPECT/CT images of ¹⁷⁷Lu-DOTA-PP-F11N in a metastatic MTC patient were also acquired. Results:^natLu-DOTA-PP-F11N is less of a substrate for neprilysins than the other analogs, whereas intracellular cysteine proteases, such as cathepsin-L, might be involved in the degradation of gastrin analogs. The uptake of all radiotracers was higher in MZ-CRC-1 tumors than in A431-CCK2R(+), apparently because of the higher number of binding sites on MZ-CRC-1 cells. ¹⁷⁷Lu-DOTA-PP-F11N had the same biodistribution as ¹⁷⁷Lu-DOTA-PP-F11; however, uptake in the MZ-CRC-1 tumors was almost double (20.7 ± 1.71 vs. 11.2 ± 2.94 %IA [percentage injected activity]/g, P = 0.0002). Coadministration of phosphoramidon or thiorphan increases ¹⁷⁷Lu-DOTA-MG11 uptake significantly in the CCK2R(+) tumors and stomach. Less profound was the effect on ¹⁷⁷Lu-DOTA-PP-F11, whereas no influence or even reduction was observed for ¹⁷⁷Lu-DOTA-PP-F11N (20.7 ± 1.71 vs. 15.6 ± 3.80 [with phosphoramidon] %IA/g, P < 0.05 in MZ-CRC-1 tumors). The first clinical data show high ¹⁷⁷Lu-DOTA-PP-F11N accumulation in tumors, stomach, kidneys, and colon. Conclusion: The performance of ¹⁷⁷Lu-DOTA-PP-F11N without protease inhibitors is as good as the performance of ¹⁷⁷Lu-DOTA-MG11 in the presence of inhibitors. The human application of single compounds without unessential additives is preferable. Preliminary clinical data spotlight the stomach as a potential dose-limiting organ besides the kidneys.

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