[68Ga]Ga-DATA5m-LM4, a PET Radiotracer in the Diagnosis of SST2R-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 [Ga-68]Ga-tracers in hospitals. We herein introduce [Ga-68]Ga-DATA(5m)-LM4 for PET/CT imaging of SST2R-positive human tumors. LM4 was obtained by 4Pal(3)/Tyr(3)-substitution in the known SST2R antagonist LM3 (H-DPhe-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH2) and DATA(5m) was coupled at the N-terminus for labeling with radiogallium (Ga-67/68). [Ga-67]Ga-DATA(5m)-LM4 was evaluated in HEK293-SST2R cells and mice models in a head-to-head comparison with [Ga-67]Ga-DOTA-LM3. Clinical grade [Ga-68]Ga-DATA(5m)-LM4 was prepared and injected in a neuroendocrine tumor (NET) patient for PET/CT imaging. DATA(5m)-LM4 displayed high SST2R binding affinity. [Ga-67]Ga-DATA(5m)-LM4 showed markedly higher uptake in HEK293-SST2R cells versus [Ga-67]Ga-DOTA-LM3 and was stable in vivo. In HEK293-SST2R xenograft-bearing mice, it achieved longer tumor retention and less kidney uptake than [Ga-67]Ga-DOTA-LM3. [Ga-68]Ga-DATA(5m)-LM4 accurately visualized tumor lesions with high contrast on PET/CT. In short, [Ga-68]Ga-DATA(5m)-LM4 has shown excellent prospects for the PET/CT diagnosis of SST2R-positive tumors, further highlighting the benefits of Ga-68 labeling in a hospital environment via the DATA(5m)-chelator route.

Automated summary

In this study, a new hybrid chelator DATA(5m) was introduced for PET/CT imaging of SST2R-positive tumors. The [Ga-68]Ga-DATA(5m)-LM4 tracer showed excellent binding affinity in cell and mouse models, and accurately visualized tumor lesions in a patient.