Novel, Potent, and Radio-Iodinatable Somatostatin Receptor 1 (sst1) Selective Analogues

The proposed sst1 pharmacophore ( J. Med. Chem. 2005, 48, 523−533) derived from the NMR structures of a family of mono- and dicyclic undecamers was used to design octa-, hepta-, and hexamers with high affinity and selectivity for the somatostatin sst1 receptor. These compounds were tested for their in vitro binding properties to all five somatostatin (SRIF) receptors using receptor autoradiography; those with high SRIF receptor subtype 1 (sst1) affinity and selectivity were shown to be agonists when tested functionally in a luciferase reporter gene assay. Des-AA1,4−6,10,12,13-[DTyr2,DAgl(NMe,2naphthoyl)8,IAmp9]-SRIF-Thr-NH2 (25) was radio-iodinated (125I-25) and specifically labeled sst1-expressing cells and tissues. 3D NMR structures were calculated for des-AA1,4−6,10,12,13-[DPhe2,DTrp8,IAmp9]-SRIF-Thr-NH2 (16), des-AA1,2,4−6,10,12,13-[DAgl(NMe,2naphthoyl)8,IAmp9]-SRIF-Thr-NH2 (23), and des-AA1,2,4−6,10,12,13-[DAgl(NMe,2naphthoyl)8,IAmp9,Tyr11]-SRIF-NH2 (27) in DMSO. Though the analogues have the sst1 pharmacophore residues at the previously determined distances from each other, the positioning of the aromatic residues in 16, 23, and 27 is different from that described earlier, suggesting an induced fit mechanism for sst1 binding of these novel, less constrained sst1-selective family members.