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 log D 7.4 ) and in vivo (biodistribution and μ SPECT/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.