Positron emission tomographic imaging of copper 64- and gallium 68-labeled chelator conjugates of the somatostatin agonist Tyr³-octreotate

The bifunctional chelator and radiometal have been shown to have a direct effect on the pharmacokinetics of somatostatin receptor (SSTR)-targeted imaging agents. We evaluated three Y3-TATE analogues conjugated to NOTA-based chelators for radiolabeling with ⁶⁴Cu and ⁶⁸Ga for small-animal positron emission tomographic/computed tomographic (PET/CT) imaging. Two commercially available NOTA analogues, p-SCN-Bn-NOTA and NODAGA, were evaluated. The p-SCN-Bn-NOTA analogues were conjugated to Y3-TATE through β-Ala and PEG₈linkages. The NODAGA chelator was directly conjugated to Y3-TATE. The analogues labeled with ⁶⁴Cu or ⁶⁸Ga were analyzed in vitro for binding affinity and internalization and in vivo by PET/CT imaging, biodistribution, and Cerenkov imaging (⁶⁸Ga analogues). We evaluated the effects of the radiometals, chelators, and linkers on the performance of the SSTR subtype 2 - targeted imaging agents and also compared them to a previously reported agent, ⁶⁴Cu-CB-TE2A-Y3-TATE. We found that the method of conjugation, particularly the length of the linkage between the chelator and the peptide, significantly impacted tumor and nontarget tissue uptake and clearance. Among the ⁶⁴Cu- and ⁶⁸Ga-labeled NOTA analogues, NODAGA-Y3-TATE had the most optimal in vivo behavior and was comparable to ⁶⁴Cu-CB-TE2A-Y3-TATE. An advantage of NODAGA-Y3-TATE is that it allows labeling with ⁶⁴Cu and ⁶⁸Ga, providing a versatile PET probe for imaging SSTr subtype 2-positive tumors.