Preclinical comparison in AR4-2J tumor-bearing mice of four radiolabeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-somatostatin analogs for tumor diagnosis and internal radiotherapy

Somatostatin analogs labeled with radionuclides are of considerable interes t in nuclear oncology as diagnostic or therapeutic tools for somatostatin r eceptor (SSTR)-expressing tumors. We investigated the suitability of DOTA ( 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid! as a replacement for the widely used diethylenetriaminepentaacetic acid, to enable stable la beling of somatostatin analogs with both therapeutic (Y-90) and diagnostic (In-111) radionuclides. The three clinically relevant somatostatin agonists , octreotide, vapreotide, and lanreotide, together with the newly designed Tyr(3)-octreotide (TyrOc), were conjugated to DOTA and labeled with Y-90 or In-111. For all DOTA-somatostatin analogs tested, irrespective of the inco rporated radionuclide, we observed favorable biodistribution profiles in AR 4-2J tumor-bearing mice: 1) a rapid clearance from all SSTR-negative tissue s except kidney; 2) a specific uptake in SSTR-positive tissues, including t umor; and 3) an excellent tumor penetration. The main route of excretion wa s via the kidneys. Nevertheless, DOTATOC was clearly superior to the other DOTA-somatostatin analogs tested, as well as OctreoScan, as indicated by th e highest tumor-to-nontarget-tissue ratio, including the tumor-to-SSTR-posi tive-tissue ratios. The presence of different SSTR subtypes in the SSTR-pos itive tissues possibly contributes to these differential uptakes. We assume that the very favorable behavior of DOTATOC in our mouse model makes this radioligand very promising for future applications in nuclear oncology.