[ 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 SSTR-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH) beyond [Ga]Ga-DATA-LM4 PET/CT (DATA, (6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate), we now introduce AAZTA-LM4 (AAZTA, 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 [In]In-AAZTA-LM4 and [Lu]Lu-AAZTA-LM4 were compared in HEK293-SSTR cells and double HEK293-SSTR/wtHEK293 tumor-bearing mice using [In]In-DOTA-LM3 and [Lu]Lu-DOTA-LM3 as references. The biodistribution of [Lu]Lu-AAZTA-LM4 was additionally studied for the first time in a NET patient. Both [In]In-AAZTA-LM4 and [Lu]Lu-AAZTA-LM4 displayed high and selective targeting of the HEK293-SSTR tumors in mice and fast background clearance via the kidneys and the urinary system. This pattern was reproduced for [Lu]Lu-AAZTA-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 [Lu]Lu-AAZTA-LM4 shows promise as a therapeutic radiopharmaceutical candidate for SSTR-expressing human NETs, based on previous [Ga]Ga-DATA-LM4 PET/CT, but further studies are needed to fully assess its clinical value. Furthermore, [In]In-AAZTA-LM4 SPECT/CT may represent a legitimate alternative diagnostic option in cases where PET/CT is not available.