The gastrin-releasing peptide receptor (GRPR) is overexpressed on various human tumors and thus has been a successful target for the detection and treatment of these cancers. Bombesin (BN) is a fourteen amino acid peptide that binds with high affinity to GRPR and radiolabeled BN analogs have been evaluated for single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging of GRPR-expressing cancers. Our laboratory was amongst the first to evaluate BN analogs radiolabeled with positron-emitting radionuclides for imaging by PET. Specifically, we used the eight C-terminal amino acids of BN (BN(7-14)) conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with copper-64 (64Cu). We have demonstrated GRPR-specific uptake and microPET imaging in mice bearing either prostate or breast cancer xenografts using various 64Cu-labeled DOTA-BN analogs. However, it is well known that metal chelate instability leads to increased radiometal absorption in non-target tissues such as the liver and kidneys, leading to decreased contrast. In particular, it has been shown that 64Cu dissociates from DOTA in vivo and transchelates to other proteins leading to high absorption in non-target tissues. Recently, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) have been conjugated to BN(7-14) and compared directly to DOTA conjugated BN(7-14). The 64Cu-labeled NOTA conjugate demonstrated lower tumor uptake than the DOTA conjugate, but also lower liver accumulation leading to higher tumor to liver ratios for the NOTA conjugate. Therefore, this proposal will focus on the development of novel bifunctional NOTA ligands that can be conjugated to BN analogs. We believe that significant improvements in NOTA conjugated BN analogs can be made since the tumor uptake of the 64Cu-labeled NOTA conjugated BN analog was less than the DOTA conjugated BN analog and that the conjugation strategy utilized one of the carboxylate arms of NOTA, reducing the coordination number. Therefore, we hypothesize that novel bifunctional NOTA ligands conjugated to BN analogs and radiolabeled with 64Cu will result in improved tumor uptake and tumor to normal tissue ratios compared to the published NOTA conjugated BN analog. A secondary hypothesis is that 68Ga- labeled NOTA conjugated BN analogs will provide high quality PET images of GRPR expressing tumors.
The Specific Aims of the proposal are: 1.) to synthesize bifunctional NOTA derivatives and characterize them as complexes with Cu(II) and Ga(III);2.) to form the 64Cu- and 68Ga-labeled complexes of the NOTA derivatives and evaluate them in vitro;3.) to conjugate the NOTA derivatives to BN analogs, radiolabel them with 64Cu or 68Ga, and evaluate them in vitro;4.) to evaluate the radiolabeled BN analogs in vivo in mice bearing tumor xenografts as radiopharmaceuticals for PET imaging of GRPR. At the conclusion of this research we expect to have developed a 64Cu-labeled BN analog and a 68Ga-labeled BN analog for PET imaging of GRPR that represents a significant improvement over the existing BN analogs that are used for PET imaging.

Public Health Relevance

At the conclusion of this research we expect to have developed a 64Cu-labeled BN analog and a 68Ga-labeled BN analog for PET imaging of GRPR that represents a significant improvement over the existing BN analogs that are used for PET imaging. These analogs should be useful for the clinical detection and staging of cancers that express GRPR.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136695-04
Application #
8266454
Study Section
Special Emphasis Panel (ZRG1-MEDI-A (09))
Program Officer
Tandon, Pushpa
Project Start
2009-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$319,464
Indirect Cost
$90,010
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Sin, Inseok; Kang, Chi Soo; Bandara, Nilantha et al. (2014) Novel hexadentate and pentadentate chelators for ??Cu-based targeted PET imaging. Bioorg Med Chem 22:2553-62
Lears, Kimberly A; Ferdani, Riccardo; Liang, Kexian et al. (2011) In vitro and in vivo evaluation of 64Cu-labeled SarAr-bombesin analogs in gastrin-releasing peptide receptor-expressing prostate cancer. J Nucl Med 52:470-7