[111In]In/[177Lu]Lu-AAZTA5-LM4 SST2R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results

Abstract

Aiming to expand the application of the SST₂R-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH₂) beyond [⁶⁸Ga]Ga-DATA^5m-LM4 PET/CT (DATA^5m, (6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate), we now introduce AAZTA⁵-LM4 (AAZTA⁵, 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 [¹¹¹In]In-AAZTA⁵-LM4 and [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 were compared in HEK293-SST₂R cells and double HEK293-SST₂R/wtHEK293 tumor-bearing mice using [¹¹¹In]In-DOTA-LM3 and [¹⁷⁷Lu]Lu-DOTA-LM3 as references. The biodistribution of [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 was additionally studied for the first time in a NET patient. Both [¹¹¹In]In-AAZTA⁵-LM4 and [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 displayed high and selective targeting of the HEK293-SST₂R tumors in mice and fast background clearance via the kidneys and the urinary system. This pattern was reproduced for [¹⁷⁷Lu]Lu-AAZTA⁵-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 [¹⁷⁷Lu]Lu-AAZTA⁵-LM4 shows promise as a therapeutic radiopharmaceutical candidate for SST₂R-expressing human NETs, based on previous [⁶⁸Ga]Ga-DATA^5m-LM4 PET/CT, but further studies are needed to fully assess its clinical value. Furthermore, [¹¹¹In]In-AAZTA⁵-LM4 SPECT/CT may represent a legitimate alternative diagnostic option in cases where PET/CT is not available.

Keywords: AAZTA5 chelator; AAZTA5-LM4; In-111; Lu-177; SPECT imaging; neuroendocrine tumors; radionuclide therapy; somatostatin subtype 2 receptor (SST2R)-antagonist; theranostics.