A new high affinity technetium analogue of bombesin containing DTPA as a pharmacokinetic modifier

The bombesin (BN)/gastrin-releasing peptide (GRP) receptor is expressed in high density on the cell surface of a variety of tumors. This makes the receptors accessible as a molecular target for the detection of lesions in which they are expressed. In this study, we describe a high affinity hydrophilic ^99mTc-labeled BN analogue, [DTPA¹, Lys³( ^99mTc-Hx-DADT), Tyr⁴]BN, having diethylenetriaminepentaacetic acid (DTPA), as a build-in pharmacokinetic modifier, to direct its excretion through the urinary system in order to lower abdominal background activity. In vitro binding studies using [ ¹²⁵I-TyT⁴] BN (K_d, 0.1 nM) and human prostate cancer PC-3 cell membranes showed that the inhibition constant (K_i) of [DTPA¹, Lys³(⁹⁹Tc-Hx-DADT), Tyr ⁴]BN was 19.9 ± 8.0 nM. Biodistribution studies in normal mice showed fast blood clearance (0.15 ± 0.01% ID/g, 4 h postinjection), low intestinal accumulation (9.16 ± 2.35% ID/g, 4 h postinjection), and significant uptake in BN/GRP receptor rich tissues such as the pancreas (21.83 ± 2.88% ID/g, 15 min postinjection). The pancreas/blood, pancreas/muscle, and pancreas/liver ratios were highest at 2 h postinjection at 23, 74, and 8.4, respectively. The uptake in the pancreas could be blocked by BN (11.96 ± 1.17 vs 0.65 ± 0.16% ID/g), partially blocked by neuromedin B (11.96 ± 1.17 vs 6.66 ± 0.51% ID/g), but not affected by somatostatin (11.96 ± 1.17 vs 12.91 ± 2.53% ID/g), indicating that the binding of [DTPA¹, Lys³(^99mTc-Hx-DADT), Tyr ⁴]BN to the receptors was specific. Scintigraphic imaging of human PC-3 prostate cancer xenografts in SCID mice gave a high target to nontarget ratio on the image. Thus, [DTPA¹, Lys³( ^99mTc-Hx-DADT), Tyr⁴]BN has the potential for imaging BN/GRP receptor-positive lesions.