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 64 Cu and 68 Ga 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 Y3TATE through b-Ala and PEG8 linkages. The NODAGA chelator was directly conjugated to Y3-TATE. The analogues labeled with 64 Cu or 68 Ga were analyzed in vitro for binding affinity and internalization and in vivo by PET/CT imaging, biodistribution, and Cerenkov imaging ( 68 Ga 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, 64 Cu-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 64 Cu- and 68 Ga-labeled NOTA analogues, NODAGA-Y3-TATE had the most optimal in vivo behavior and was comparable to 64 Cu-CB-TE2A-Y3-TATE. An advantage of NODAGA-Y3-TATE is that it allows labeling with 64 Cu and 68 Ga, providing a versatile PET probe for imaging SSTr subtype 2–positive tumors.