title: 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.
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 Tyr3-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, Tyr3-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 64Cu(II). The in vitro receptor binding, in vitro tumor cell uptake, and in vivo distribution properties of 64Cu-labeled TETA-Y3-OC and TETA-TATE were compared to those of [64Cu]TETA-OC and [64Cu]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 [64Cu]TETA-Y3-TATE (60. 75 +/- 1.21%) and [64Cu]TETA-TATE (55.62 +/- 0.16%) into AR42J rat pancreatic tumor cells over a 2-h time period were higher than those of [64Cu]TETA-Y3-OC (47.20 +/- 1.20%) and [64Cu]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 64Cu-labeled peptides in somatostatin-rich tissues, including the pituitary, adrenals, pancreas, and tumor. The structure-activity relationships of the four 64Cu-labeled peptides did not show consistent trends in all target tissues, but [64Cu]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 [64Cu]TETA-Y3-TATE justifies the selection of this agent for future PET imaging and targeted radiotherapy studies.
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, Campus Box 8225, St. Louis, Missouri 63110, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Lewis
authors.forename: M R
authors.initials: MR
authors.lastname: Lewis
authors.forename: A
authors.initials: A
authors.lastname: Srinivasan
authors.forename: M A
authors.initials: MA
authors.lastname: Schmidt
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: C J
authors.initials: CJ
authors.lastname: Anderson
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D011917:Rats, Inbred Lew; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D008024:Ligands; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C118758:copper(64)TETA-phenyalanyl-tyrosyl(3)-octreotate; D013004:Somatostatin