[ 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.