Radiolabeled
bombesin (BBS) analogues are promising
pharmaceuticals for imaging of
cancer cells expressing
gastrin-releasing peptide receptors (GRPR). However, most of the radiolabeled BBS derivatives show a high accumulation of activity in the liver and a strong hepatobiliary excretion, both unfavorable for imaging and
therapy of abdominal lesions. For this reason, we introduced hydrophilic carbohydrated linker moieties into our BBS analogues to reduce the abdominal accumulation and to improve the
tumor-to-background ratios. A stabilized BBS(7-14) sequence bearing the (NalphaHis)Ac-
chelator was modified with
amino acid linkers containing a
lysine or
propargylglycine residue. The epsilon-amino group of a
lysine was either coupled to
shikimic acid or reacted with
glucose to form the Amadori conjugate. Alternatively, a
glucose was attached to the
peptide via "click" chemistry with the
propargylglycine side chain. The
peptides were synthesized on
Rink amide resin using solid-phase peptide synthesis and labeled with 99mTc using the tricarbonyl technique. Binding and degradation were tested in Vitro in GRPR-expressing PC-3 cells. Biodistribution and SPECT/CT imaging studies were performed in nude mice bearing PC-3
tumor xenografts. The new
peptides showed a log D between -0.2 and -0.5 and kept the high affinity for GRPR with Kd values of <0.5 nM. In Vitro, they were rapidly internalized into the
tumor cells and showed an increased cellular retention and stability (t(1/2 )>35 min). In ViVo, all new compounds exhibited higher
tumor-to-background ratios compared to the nonglycated reference. Thus, the best results were obtained with the
triazole coupled
glucose with a 4-fold increased uptake and retention in
tumor tissue (3.6 and 2.5%ID/g at 1.5 h and 5 h p.i, respectively) and a significantly reduced accumulation in the liver (0.6 vs 2.4%ID/g, 1.5 h p.i., respectively). Apart from higher
tumor-to-liver ratios (17-fold, 1.5 h p.i.), both
tumor-to-kidney and
tumor-to-blood ratios could be significantly improved by
a factor of 1.5 and 2.7, respectively (1.5 h p.i., P<0.05). The imaging studies proved the reduction of abdominal background, and
tumor xenografts could clearly be visualized. In conclusion, the introduction of a carbohydrated linker substantially improved the biodistribution properties of BBS analogues labeled with the 99mTc-tricarbonyl core.