title: A new high affinity technetium analogue of bombesin containing DTPA as a pharmacokinetic modifier.
abstract: 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 (99m)Tc-labeled BN analogue, [DTPA(1), Lys(3)((99m)Tc-Hx-DADT), Tyr(4)]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 [(125)I-Tyr(4)]BN (K(d), 0.1 nM) and human prostate cancer PC-3 cell membranes showed that the inhibition constant (K(i)) of [DTPA(1), Lys(3)((99)Tc-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 [DTPA(1), Lys(3)((99m)Tc-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, [DTPA(1), Lys(3)((99m)Tc-Hx-DADT), Tyr(4)]BN has the potential for imaging BN/GRP receptor-positive lesions.
authors.affiliation: Department of Environmental Health Sciences, The Johns Hopkins Medical Institutions, 615 North Wolfe Street, Room E6632, Baltimore, Maryland 21205, USA.
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
authors.forename: Andrew
authors.initials: A
authors.lastname: Luu
authors.forename: Kwamena E
authors.initials: KE
authors.lastname: Baidoo
authors.forename: Hossein
authors.initials: H
authors.lastname: Hashemzadeh-Gargari
authors.forename: Ming-Kai
authors.initials: MK
authors.lastname: Chen
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.forename: Martin
authors.initials: M
authors.lastname: Pomper
authors.forename: Michael
authors.initials: M
authors.lastname: Carducci
authors.forename: Henry N
authors.initials: HN
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001839:Bombesin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D004369:Pentetic Acid / Q000493:pharmacokinetics*; D013667:Technetium / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D013667:Technetium; D004369:Pentetic Acid; D001839:Bombesin