A new high affinity technetium-99m-bombesin analogue with low abdominal accumulation.
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 (Ki) 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.
Lin
Kuo-Shyan
KS
Department of Environmental Health Sciences, The Johns Hopkins Medical Institutions, 615 North Wolfe Street, Baltimore, Maryland 21205, USA.
Luu
Andrew
A
Baidoo
Kwamena E
KE
Hashemzadeh-Gargari
Hossein
H
Chen
Ming-Kai
MK
Brenneman
Kenneth
K
Pili
Roberto
R
Pomper
Martin
M
Carducci
Michael A
MA
Wagner
Henry N
HN
D000005:Abdomen / Q000000981:diagnostic imaging / Q000502:physiology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001839:Bombesin / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D015287:Neurokinin B / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000378:metabolism*; D018004:Receptors, Bombesin / Q000378:metabolism; D013004:Somatostatin / Q000494:pharmacology; D017256:Technetium Tc 99m Sestamibi / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D013004:Somatostatin; D015287:Neurokinin B; C038393:neuromedin B; D017256:Technetium Tc 99m Sestamibi; D001839:Bombesin