[Ga]Ga-DATA-LM4, a PET Radiotracer in the Diagnosis of SSTR-Positive Tumors: Preclinical and First Clinical Results.

Radiolabeled somatostatin subtype 2 receptor (SST2R)-antagonists have shown advantageous profiles for cancer theranostics compared with agonists. On the other hand, the newly introduced hybrid chelator (6-pentanoic acid)-6-(amino)methyl-1,4-diazepinetriacetate (DATA) rapidly binds Ga-68 (t: 67.7 min) at much lower temperature, thus allowing for quick access to "ready-for-injection" [Ga]Ga-tracers in hospitals. We herein introduce [Ga]Ga-DATA-LM4 for PET/CT imaging of SSTR-positive human tumors. LM4 was obtained by 4Pal/Tyr-substitution in the known SSTR antagonist LM3 (H-DPhe-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH) and DATA was coupled at the N-terminus for labeling with radiogallium (Ga-67/68). [Ga]Ga-DATA-LM4 was evaluated in HEK293-SSTR cells and mice models in a head-to-head comparison with [Ga]Ga-DOTA-LM3. Clinical grade [Ga]Ga-DATA-LM4 was prepared and injected in a neuroendocrine tumor (NET) patient for PET/CT imaging. DATA-LM4 displayed high SSTR binding affinity. [Ga]Ga-DATA-LM4 showed markedly higher uptake in HEK293-SSTR cells versus [Ga]Ga-DOTA-LM3 and was stable in vivo. In HEK293-SSTR xenograft-bearing mice, it achieved longer tumor retention and less kidney uptake than [Ga]Ga-DOTA-LM3. [Ga]Ga-DATA-LM4 accurately visualized tumor lesions with high contrast on PET/CT. In short, [Ga]Ga-DATA-LM4 has shown excellent prospects for the PET/CT diagnosis of SSTR-positive tumors, further highlighting the benefits of Ga-68 labeling in a hospital environment via the DATA-chelator route.