[(68)Ga]Ga-DATA(5m)-LM4, a PET Radiotracer in the Diagnosis of SST(2)R-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(5m)) rapidly binds Ga-68 (t(1/2): 67.7 min) at much lower temperature, thus allowing for quick access to “ready-for-injection” [(68)Ga]Ga-tracers in hospitals. We herein introduce [(68)Ga]Ga-DATA(5m)-LM4 for PET/CT imaging of SST(2)R-positive human tumors. LM4 was obtained by 4Pal(3)/Tyr(3)-substitution in the known SST(2)R antagonist LM3 (H-DPhe-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH(2)) and DATA(5m) was coupled at the N-terminus for labeling with radiogallium (Ga-67/68). [(67)Ga]Ga-DATA(5m)-LM4 was evaluated in HEK293-SST(2)R cells and mice models in a head-to-head comparison with [(67)Ga]Ga-DOTA-LM3. Clinical grade [(68)Ga]Ga-DATA(5m)-LM4 was prepared and injected in a neuroendocrine tumor (NET) patient for PET/CT imaging. DATA(5m)-LM4 displayed high SST(2)R binding affinity. [(67)Ga]Ga-DATA(5m)-LM4 showed markedly higher uptake in HEK293-SST(2)R cells versus [(67)Ga]Ga-DOTA-LM3 and was stable in vivo. In HEK293-SST(2)R xenograft-bearing mice, it achieved longer tumor retention and less kidney uptake than [(67)Ga]Ga-DOTA-LM3. [(68)Ga]Ga-DATA(5m)-LM4 accurately visualized tumor lesions with high contrast on PET/CT. In short, [(68)Ga]Ga-DATA(5m)-LM4 has shown excellent prospects for the PET/CT diagnosis of SST(2)R-positive tumors, further highlighting the benefits of Ga-68 labeling in a hospital environment via the DATA(5m)-chelator route.