SST3-Selective Potent Peptidic Somatostatin Receptor Antagonists

A family of octapeptide derivatives of somatostatin cyclized via a disulfide bridge (des-AA1,2,4,5,12,13[D-2Nal8]-somatostatin-14, ODN-8) was identified that has high affinity and selectivity for the human sst3somatostatin receptor subtype transfected in CCL39 cells. The binding affinity of carbamoyl-des-AA1,2,4,5,12,13[D-Cys3,Tyr7,D-Agl8(Me, 2-naphthoyl)]-somatostatin-14 (sst3-ODN-8) is equal to that of somatostatin-28 for sst3and less than one-thousandth that for the other four somatostatin receptor subtypes. Compound sst3-ODN-8 potently reverses the somatostatin-28-induced inhibition of forskolin-stimulated camp production (pKB= 9.07) and reverses the somatostatin-28-induced stimulation of phospholipase C activity (pKi= 9.22) in sst3- transfected CCL39 cells. [125I-Tyr7]sst3-ODN-8 selectively labels sst3-expressing cells with subnanomolar binding affinity (KD= 0.27 nM). With the use of this radioligand, sst3-expressing human tumors, articularly inactive pituitary adenomas, can be identified with receptor autoradiography; moreover, areas of the human lymphoreticular system express sst3binding sites selectively displaced by nanomolar concentrations of sst3-ODN-8. Based on the structure-activity relationship of selected analogs substituted at position 3, 7, and 8, we hypothesize that the basis for sst3selectivity, high affinity, and possibly antagonism resides in the ring size of the analog and the unique conformational and structural character of the N-methylated amino-2-naphthoyl side chain of aminoglycine at position 8 and not in the Tyr7substitution or in the D-configuration at position 3. The family of labeled and unlabeled sst3-ODN-8 analogs represents highly innovative, potent, and specific sst3-selective antagonist tools for the study of sst3-mediated physiological and pathophysiological conditions that may suggest novel clinical applications.