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

Abstract

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.

Evaluation of a 1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid–Conjugated Bombesin-Based Radioantagonist for the Labeling with Single-Photon Emission Computed Tomography, Positron Emission Tomography, and Therapeutic Radionuclides

“…Bombesin-based radioagonists as targeting agents for prostate cancer have been described in preclinical (17)(18)(19)(20)(21)(22)(23)(24) and clinical studies (25)(26)(27). The first recently published [ 99m Tc]-labeled bombesinbased radioantagonist showed a 2-to 4-fold higher tumor uptake than the agonist (31).…”

“…They show antitumor activity in murine and human tumors (14)(15)(16). Moreover, the development of radiolabeled peptides for imaging and targeted radionuclide therapy has been advanced in recent years (17)(18)(19)(20)(21)(22)(23)(24). Clinical studies with […”

Molecular Imaging of Metastatic Potential

“…Bombesin, a 14-amino-acid neuropeptide, is known to have high-affinity binding to gastrin-releasing peptide receptors. A recently developed 99m Tc-labeled bombesin analog has been studied in preclinical tumor models and found to have a more favorable biodistribution than an earlier 99m Tc-bombesin reported by the same authors (137). 64 Cu-, 68 Ga-and 18 F-labeled bombesin analogs for PET have also been reported (138)(139)(140)(141).…”

Targeting prostate cancer with radiolabelled bombesins

“…By coupling DADT to [DTPA 1 ,Lys 3 ,Tyr 4 ]BB a much more hydrophilic radiotracer was obtained due to the presence of four pendant DTPA 1 -carboxylate groups. This analogue showed good GRP-R-targeting in mice and excretion via the renal pathway [28,29] . Neutral 99m Tc V O 3+ -complexes are also obtained by coupling tripeptide N 3 S-donors to BB or BB (7)(8)(9)(10)(11)(12)(13)(14), either directly or via a spacer [30][31][32][33][34] .…”