A new high affinity technetium-99m-bombesin analogue with low abdominal accumulation

Tc-99m-labeled bombesin analogues have shown promise for noninvasive detection of many tumors that express bombesin (BN)/gastrin-releasing peptide (GRP) receptors. Tc-99m-labeled peptides, however, have a tendency to accumulate in the liver and intestines due to hepatobiliary clearance as a result of the lipophilicity of the Tc-99m chelates. This makes the imaging of lesions in the abdominal area difficult. In this study, we have synthesized a new high affinity Tc-99m-labeled BN analogue, [DTPA(1), Lys(3)(Tc-99m-Pm-DADT), Tyr(4)]BN, having a built-in pharmacokinetic modifier, DTPA, and labeled with Tc-99m using a hydrophilic diaminedithiol chelator (Pm-DADT) to effect low hepatobiliary clearance. In vitro binding studies using human prostate cancer PC-3 cell membranes showed that the inhibition constant (K-i) for [DTPA(1), Lys(3)(Tc-99-Pm-DADT), Tyr(4)]BN was 4.1 +/- 1.4 nM. Biodistribution studies of [DTPA(1), Lys(3)(Tc-99m-Pm-DADT), Tyr(4)]BN in normal mice showed very low accumulation of radioactivity in the liver and intestines (1.32 +/- 0.13 and 4.58 +/- 0.50% ID, 4 h postinjection, respectively). There was significant uptake (7.71 +/- 1.37% ID/g, 1 h postinjection) in the pancreas which expresses BN/GRP receptors. The uptake in the pancreas could be blocked by BN, partially blocked by neuromedin B, but not affected by somatostatin, indicating that the in vivo binding was BN/GRP receptor specific. Scintigraphic images showed specific, high contrast delineation of prostate cancer PC-3 xenografts in SCID mice. Thus, the new peptide has a great potential for imaging BN/GRP receptor-positive cancers located even in the abdomen.