Optimization of the Pharmacokinetic Profile of [(99m)Tc]Tc-N(4)-Bombesin Derivatives by Modification of the Pharmacophoric Gln-Trp Sequence

Current radiolabeled gastrin-releasing peptide receptor (GRPR) ligands usually suffer from high accumulation in GRPR-positive organs (pancreas, stomach), limiting tumor-to-background contrast in the abdomen. In novel N(4)-bombesin derivatives this was addressed by substitutions at the Gln(7)-Trp(8) site within the MJ9 peptide (H-Pip(5)-phe(6)-Gln(7)-Trp(8)-Ala(9)-Val(10)-Gly(11)-His(12)-Sta(13)-Leu(14)-NH(2)) either by homoserine (Hse(7)), β-(3-benzothienyl) alanine (Bta(8)) or α-methyl tryptophan (α-Me-Trp(8)), with the aim of optimizing pharmacokinetics. We prepared and characterized the peptide conjugates 6-carboxy-1,4,8,11-tetraazaundecane (N(4))-asp-MJ9, N(4)-asp-[Bta(8)]MJ9, N(4)-[Hse(7)]MJ9 and N(4)-[α-Me-Trp(8)]MJ9, and evaluated these compounds in vitro (GRPR affinity via IC(50,inverse); internalization; lipophilicity via logD(7.4)) and in vivo (biodistribution and μSPECT/CT studies at 1 h post injection (p.i.) in PC-3 tumor-bearing CB17-SCID mice). (99m)Tc-labeling resulted in radiochemical yields (RCYs) > 95%. All (99m)Tc-labeled MJ9 analogues showed comparable or higher GRPR affinity than the external reference [(99m)Tc]Tc-Demobesin 4. Receptor-bound fractions were noticeably higher than that of the reference. Despite a slightly enhanced lipophilicity, all novel MJ9 derivatives revealed improved in vivo pharmacokinetics compared to the reference. The Bta(8)-modified ligand revealed the most favorable tumor-to-abdomen contrast at 1 h p.i. Substitutions at the Gln(7)-Trp(8) site within GRPR ligands hold great potential to modify pharmacokinetics for improved imaging.