Comparison of Four 64Cu-Labeled Somatostatin Analogues in Vitro and in a Tumor-Bearing Rat Model: Evaluation of New Derivatives for Positron Emission Tomography Imaging and Targeted Radiotherapy

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Abstract
Previous studies have shown that modification of the somatostatin analogue octreotide (OC), by substitution of tyrosine for phenylalanine at position 3 and of a C-terminal carboxylic acid for an alcohol, to give Tyr 3 -octreotate (Y3-TATE) improved uptake of the peptide in somatostatin receptor-positive tissues. To determine which substitution best accounts for increased target tissue uptake, the peptides containing single modifications, Tyr 3 -octreotide (Y3-OC) and octreotate (TATE), were synthesized. These peptides were conjugated to the macrocyclic chelating agent 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA) and radiolabeled with 64 Cu(II). The in vitro receptor binding, in vitro tumor cell uptake, and in vivo distribution properties of 64 Cu-labeled TETA-Y3-OC and TETA-TATE were compared to those of ( 64 Cu)TETA-OC and ( 64 Cu)TETA-Y3-TATE. Cu-TETA-TATE (IC50 ) 0.297 ( 0.0055 nM) and Cu-TETA-Y3-TATE (IC50 ) 0.308 ( 0.0375 nM) displayed significantly higher binding affinity to somatostatin receptors on CA20948 rat pancreatic tumor membranes than Cu-TETA- Y3-OC (IC50 ) 0.397 ( 0.0206 nM) and Cu-TETA-OC (IC50 ) 0.498 ( 0.039 nM). Similarly, the uptakes of ( 64 Cu)TETA-Y3-TATE (60.75 ( 1.21%) and ( 64 Cu)TETA-TATE (55.62 ( 0.16%) into AR42J rat pancreatic tumor cells over a 2-h time period were higher than those of ( 64 Cu)- TETA-Y3-OC (47.20 ( 1.20%) and ( 64 Cu)TETA-OC (34.07 ( 2.24%). The in vitro results suggest that the C-terminal carboxylate may contribute more to enhanced receptor binding and tumor cell uptake than the substitution at the 3-position. Biodistributions in CA20948 tumor-bearing rats showed receptor-mediated uptake of the 64 Cu-labeled peptides in somatostatin-rich tissues, including the pituitary, adrenals, pancreas, and tumor. The structure-activity relationships of the four 64 Cu-labeled peptides did not show consistent trends in all target tissues, but ( 64 - Cu)TETA-Y3-TATE exhibited tumor uptake 1.75-3.5 times higher than the other derivatives at 4 h postinjection. The greater tumor retention of ( 64 Cu)TETA-Y3-TATE justifies the selection of this agent for future PET imaging and targeted radiotherapy studies.

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