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

Kuo Shyan Lin, Andrew Luu, Kwamena E. Baidoo, Hossein Hashemzadeh-Gargari, Ming Kai Chen, Roberto Pili, Martin Pomper, Michael Carducci, Henry N. Wagner

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 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 (Kd, 0.1 nM) and human prostate cancer PC-3 cell membranes showed that the inhibition constant (Ki) 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.

Original languageEnglish (US)
Pages (from-to)1416-1423
Number of pages8
JournalBioconjugate Chemistry
Volume15
Issue number6
DOIs
StatePublished - Nov 2004
Externally publishedYes

Fingerprint

Technetium
Bombesin
Pharmacokinetics
Peptides
Bombesin Receptors
Acids
Pancreas
Blood
Imaging techniques
Cell membranes
Liver
Muscle
Tumors
Tissue
Prostatic Neoplasms
SCID Mice
Gastrins
Somatostatin
Heterografts
Cell Count

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Clinical Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

Lin, K. S., Luu, A., Baidoo, K. E., Hashemzadeh-Gargari, H., Chen, M. K., Pili, R., ... Wagner, H. N. (2004). A new high affinity technetium analogue of bombesin containing DTPA as a pharmacokinetic modifier. Bioconjugate Chemistry, 15(6), 1416-1423. https://doi.org/10.1021/bc0498267

A new high affinity technetium analogue of bombesin containing DTPA as a pharmacokinetic modifier. / Lin, Kuo Shyan; Luu, Andrew; Baidoo, Kwamena E.; Hashemzadeh-Gargari, Hossein; Chen, Ming Kai; Pili, Roberto; Pomper, Martin; Carducci, Michael; Wagner, Henry N.

In: Bioconjugate Chemistry, Vol. 15, No. 6, 11.2004, p. 1416-1423.

Research output: Contribution to journalArticle

Lin, KS, Luu, A, Baidoo, KE, Hashemzadeh-Gargari, H, Chen, MK, Pili, R, Pomper, M, Carducci, M & Wagner, HN 2004, 'A new high affinity technetium analogue of bombesin containing DTPA as a pharmacokinetic modifier', Bioconjugate Chemistry, vol. 15, no. 6, pp. 1416-1423. https://doi.org/10.1021/bc0498267
Lin, Kuo Shyan ; Luu, Andrew ; Baidoo, Kwamena E. ; Hashemzadeh-Gargari, Hossein ; Chen, Ming Kai ; Pili, Roberto ; Pomper, Martin ; Carducci, Michael ; Wagner, Henry N. / A new high affinity technetium analogue of bombesin containing DTPA as a pharmacokinetic modifier. In: Bioconjugate Chemistry. 2004 ; Vol. 15, No. 6. pp. 1416-1423.
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AU - Chen, Ming Kai

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AU - Wagner, Henry N.

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N2 - 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 (Kd, 0.1 nM) and human prostate cancer PC-3 cell membranes showed that the inhibition constant (Ki) 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.

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