[(111)In]In/[(177)Lu]Lu-AAZTA(5)-LM4 SST(2)R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results

Aiming to expand the application of the SST(2)R-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH(2)) beyond [(68)Ga]Ga-DATA(5m)-LM4 PET/CT (DATA(5m), (6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate), we now introduce AAZTA(5)-LM4 (AAZTA(5), 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine), allowing for the convenient coordination of trivalent radiometals of clinical interest, such as In-111 (for SPECT/CT) or Lu-177 (for radionuclide therapy). After labeling, the preclinical profiles of [(111)In]In-AAZTA(5)-LM4 and [(177)Lu]Lu-AAZTA(5)-LM4 were compared in HEK293-SST(2)R cells and double HEK293-SST(2)R/wtHEK293 tumor-bearing mice using [(111)In]In-DOTA-LM3 and [(177)Lu]Lu-DOTA-LM3 as references. The biodistribution of [(177)Lu]Lu-AAZTA(5)-LM4 was additionally studied for the first time in a NET patient. Both [(111)In]In-AAZTA(5)-LM4 and [(177)Lu]Lu-AAZTA(5)-LM4 displayed high and selective targeting of the HEK293-SST(2)R tumors in mice and fast background clearance via the kidneys and the urinary system. This pattern was reproduced for [(177)Lu]Lu-AAZTA(5)-LM4 in the patient according to SPECT/CT results in a monitoring time span of 4–72 h pi. In view of the above, we may conclude that [(177)Lu]Lu-AAZTA(5)-LM4 shows promise as a therapeutic radiopharmaceutical candidate for SST(2)R-expressing human NETs, based on previous [(68)Ga]Ga-DATA(5m)-LM4 PET/CT, but further studies are needed to fully assess its clinical value. Furthermore, [(111)In]In-AAZTA(5)-LM4 SPECT/CT may represent a legitimate alternative diagnostic option in cases where PET/CT is not available.