A New High Affinity Technetium-99m-Bombesin Analogue with Low Abdominal Accumulation

• Published in: Bioconjugate chemistry 2005-01, Vol.16 (1), p.43-50
• Main Authors: Lin, Kuo-Shyan, Luu, Andrew, Baidoo, Kwamena E, Hashemzadeh-Gargari, Hossein, Chen, Ming-Kai, Brenneman, Kenneth, Pili, Roberto, Pomper, Martin, Carducci, Michael A, Wagner, Henry N
• Format: Article
• Language: English
• Subjects: Abdomen - diagnostic imaging; Abdomen - physiology; Animals; Binding Sites - drug effects; Bombesin - metabolism; Cancer; Chemistry; Disease Models, Animal; Humans; Male; Mice; Neoplasm Transplantation; Neurokinin B - analogs & derivatives; Neurokinin B - pharmacology; Peptides; Prostatic Neoplasms - diagnostic imaging; Prostatic Neoplasms - metabolism; Radionuclide Imaging; Radiopharmaceuticals - metabolism; Receptors, Bombesin - metabolism; Somatostatin - pharmacology; Technetium Tc 99m Sestamibi - metabolism; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc049820h

99mTc-labeled bombesin analogues have shown promise for noninvasive detection of many tumors that express bombesin (BN)/gastrin-releasing peptide (GRP) receptors. 99mTc-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 99mTc chelates. This makes the imaging of lesions in the abdominal area difficult. In this study, we have synthesized a new high affinity 99mTc-labeled BN analogue, [DTPA1, Lys3(99mTc-Pm-DADT), Tyr4]BN, having a built-in pharmacokinetic modifier, DTPA, and labeled with 99mTc 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 [DTPA1, Lys3(99Tc-Pm-DADT), Tyr4]BN was 4.1 ± 1.4 nM. Biodistribution studies of [DTPA1, Lys3(99mTc-Pm-DADT), Tyr4]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.