99mTc(CO)3-DTMA bombesin conjugates having high affinity for the GRP receptor

Lane, Stephanie R.; Veerendra, Bhadrasetty; Rold, Tammy L.; Sieckman, Gary L.; Hoffman, Timothy J.; Jurisson, Silvia S.; Smith, Charles J.

doi:10.1016/j.nucmedbio.2007.11.007

Next »Nuclear Medicine and Biology
Volume 35, Issue 3 , Pages 263-272, April 2008

^99mTc(CO)₃-DTMA bombesin conjugates having high affinity for the GRP receptor

Stephanie R. Lane
- Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA
- Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
Bhadrasetty Veerendra
- Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211, USA
Tammy L. Rold
- Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO 65211, USA
Gary L. Sieckman
- Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA
Timothy J. Hoffman
- Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA
- The Radiopharmaceutical Sciences Institute, University of Missouri-Columbia School of Medicine, Columbia, MO 65211, USA
- Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
Silvia S. Jurisson
- Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
Charles J. Smith
- Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211, USA
- Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA
- University of Missouri Research Reactor Center, University of Missouri-Columbia, Columbia, MO 65211, USA
- The Radiopharmaceutical Sciences Institute, University of Missouri-Columbia School of Medicine, Columbia, MO 65211, USA
- Corresponding author. Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA. Tel.: +1 573 814 6000x3683; fax: +1 573 882 1663.

Received 2 October 2007; received in revised form 26 October 2007; accepted 17 November 2007.

Abstract

Introduction

Targeted diagnosis of specific human cancer types continues to be of significant interest in nuclear medicine. ^99mTc is ideally suited as a diagnostic radiometal for in vivo tumor targeting due to its ideal physical characteristics and diverse labeling chemistries in numerous oxidation states.

Methods

In this study, we report a synthetic approach toward design of a new tridentate amine ligand for the organometallic aqua-ion [^99mTc(H₂O)₃(CO)₃]⁺. The new chelating ligand framework, 2-(N,N′-Bis(tert-butoxycarbonyl)diethylenetriamine) acetic acid (DTMA), was synthesized from a diethylenetriamine precursor and fully characterized by mass spectrometry and nuclear magnetic resonance spectroscopy (¹H and ¹³C). DTMA was conjugated to H₂N-(X)-BBN(7-14)NH₂, where X=an amino acid or aliphatic pharmacokinetic modifier and BBN=bombesin peptide, by means of solid phase peptide synthesis. DTMA-(X)-BBN(7-14)NH₂ conjugates were purified by reversed-phase high-performance chromatography and characterized by electrospray-ionization mass spectrometry.

Results

The new conjugates were radiolabeled with [^99mTc(H₂O)₃(CO)₃]⁺ produced via Isolink radiolabeling kits to produce [^99mTc(CO)₃-DTMA-(X)-BBN(7-14)NH₂]. Radiolabeled conjugates were purified by reversed-phase high-performance chromatography. Effective receptor binding behavior was evaluated in vitro and in vivo.

Conclusions

[^99mTc(CO)₃-DTMA-(X)-BBN(7-14)NH₂] conjugates displayed very high affinity for the gastrin releasing peptide receptor in vitro and in vivo. Therefore, these conjugates hold some propensity to be investigated as molecular imaging agents that specifically target human cancers uniquely expressing the gastrin releasing peptide receptor subtypes.

Keywords: Bombesin, Prostate, Tridentate, Tricarbonyl, Internalization, Biodistribution