Effects of Chelator Modifications on 68Ga-Labeled [Tyr3]Octreotide Conjugates

Somatostatin receptors (SSTR) have been reported as promising targets for imaging agents for cancer. Recently, Ga-68-DOTATOC-based PET imaging has been used successfully for diagnosis and management of SSTR-expressing tumors. The purpose of this study was to evaluate the influence of chelator modifications and charge on Ga-68-labeled peptide conjugates. We have synthesized a series of [Tyr(3)]octreotide conjugates that consisted of different NOTA-based chelators with two to five carboxylate moieties, and compared our results with Ga-68-DOTATOC in both in vitro and in vivo studies. With the exception of Ga-68-1 (three carboxylates), the increased number of carboxylates on the NOTA-based chelators resulted in a reduced binding affinity and internalization. Additionally, the tumor uptake for Ga-68-2 (four carboxylates) and Ga-68-3 (five carboxylates) was reduced compared to that of Ga-68-DOTATOC (three carboxylates) and Ga-68-NO2ATOC (two carboxylates) and Ga-68-1 (three carboxylates) at 2 h p.i. suggesting the presence of an optimal charge for this compound. Chelator modifications can lead to the altered pharmacokinetics. These results may impact further design considerations for peptide-based imaging agents.