Design and in vitro Characterization of Highly Sst2-selective Somatostatin Antagonists Suitable for Radio-Targeting

Radiolabeled sst 2 and sst 3 antagonists are better candidates for tumor targeting than agonists with comparable binding characteristics. 1 Because the majority of neuroendocrine tumors express sst 2 , we used the known antagonists Acetyl-pNO 2 Phe 2 -c[ d Cys 3 -Tyr 7 - d Trp 8 -Lys 9 -Thr 10 -Cys 14 ]- d Tyr 15 -NH 2 ( 1 ) 2 , 3 and H-Cpa 2 -c[ d Cys 3 -Tyr 7 - d Trp 8 -Lys 9 -Thr 10 -Cys 14 ]-2Nal 15 -NH 2 ( 7) 4 as leads for analogues with increased sst 2 binding affinity and selectivity. Among the 32 analogues reported here, DOTA-pNO 2 Phe-c[ d Cys-Tyr- d Aph(Cbm)-Lys-Thr-Cys]- d Tyr-NH 2 ( 3) and DOTA-Cpa-c[ d Cys-Aph(Hor)- d Aph(Cbm)-Lys-Thr-Cys]- d Tyr-NH 2 ( 31) had the highest sst 2 binding affinity and selectivity. All of the analogues tested kept their sst 2 antagonistic properties (i.e. did not affect calcium release in vitro and competitively antagonized the agonistic effect of [Tyr 3 ]-octreotide). Moreover, in an immunofluorescence-based internalization assay, the new analogues prevented sst 2 internalization induced by the sst 2 agonist [Tyr 3 ]-octreotide, without being active by themselves. In conclusion, several analogues (in particular 3 , 31 and 32 ) have outstanding sst 2 binding and functional antagonistic properties and, because of their DOTA moiety, are excellent candidates for in vivo targeting of sst 2 -expressing cancers.