PET/Optical Imaging Probe Section

Contents

• Research Interests
• Facilities
• Staff

Research Interests 

The PET/Optical Imaging Probe Section has research interests in the development of novel methods for incorporation of radionuclides and fluorophores into molecules for the study of biologically important processes. Our research efforts are driven by the desire to better understand the biology and translate our work into clinically relevant human diseases. Thus, we seek to collaborate with clinicians that share our goal of providing new imaging tools with utility in patients. We have interest in designing probes with applications to many important biological processes, including but not limited to inflammation, metabolism, proliferation, angiogenesis, metastasis, lymphogenesis, hypoxia, and apoptosis.

Small Molecule Probes

There are numerous targets for drug-like molecules that are of interest for their role in human disease. Imaging studies can be utilized as a research tool to help determine optimum drug dosing and elucidation of biochemical function. In addition, imaging studies can be clinically relevant for diagnosis of disease, staging of disease, and treatment response. We have developed methods for the incorporation of fluorine-18 and bromine-76 into small molecule tracers with applications for studies of brain function and disease and for diagnosis, staging, and treatment management in oncology. Adenosine A2a and A3 receptors, corticotrophin releasing hormone (CRH) ligands, muscarinic, and serotonin ligands, CXCR4 are a few examples.

Targeting Employing Proteins and Peptides

Antibodies are the most specific molecules for binding to their particular antigen. Imaging of radiolabeled antibodies has been investigated for many years. The challenge with antibody imaging is the long half-life in the blood. One approach is to radiolabel with longer lived radionuclides. The non-traditional PET radioisotopes such as Br-76, Y-86, Cu-64, Zr-89, and I-124 and SPECT radionuclides such as I-123 and In-111 offer longer half-lives that may be more useful for this application. An alternative approach is to develop smaller proteins or peptides that display high binding specificity but have more rapid pharmacokinetics. We have developed or adapted from the literature small organic prosthetic groups labeled with fluorine-18 or Br-76 for conjugation with proteins and peptides. Peptides and proteins can also be functionalized first in order to allow site specific labeling with radiohalides or radiometals as well as fluorophores.

Analytical Techniques

Our laboratory has been one of the leaders in the use of highly sensitive high resolution mass spectrometry coupled with HPLC to identify radiometabolites from novel imaging agents. In the development of novel small molecule imaging agents, we typically use hepatocytes from rat, monkey, and human to generate metabolites. The metabolites are analyzed by HPLC-MS and structures are proposed based on acquired data and literature precedence. The results allow a qualitative assessment of the propensity of radiolabeled metabolites to interfere with interpretation of images, an assessment of species differences anticipated as the compounds move toward eventual clinical use, and can assist in the preparation of improved ligands by modification of chemical structure to alter the metabolism. The mass spectrometry results have been utilized to assist in the development and validation of TLC and/or extraction methods to provide parent corrected plasma input functions for PET modeling. The high sensitivity of the mass spectrometer for some chemical structures can allow determination of biodistribution without the need to synthesize the radiolabeled compound. We intend to pursue this technology to conduct metabolite analysis of radiolabeled and fluorescently labeled peptides and proteins.

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Facilities

PET/Optical Imaging Probe Section is physically located in building 10; radiochemical laboratories are located within the NIH cyclotron facility. The laboratory has one hot cell for conducting high level radiochemical syntheses using Br-76 and Zr-89. A second hot cell houses an automated GE synthesis module for the high radioactivity level syntheses of fluorine-18 radiolabeled. In addition, an automated PET synthetic module with multiple reactors was built with in-house expertise. We have the ability to conduct low-level manual synthesis in shielded chemical fume hoods including thermal and microwave assisted synthesis.

The group has significant experience in conducting multistep chemical synthesis of small drug-like molecules and developing strategies for incorporation of F-18 or Br-76 radionuclides. The group possesses experience in solid phase peptide synthesis, chelator conjugation and fluorphore coupling and modification. The laboratory is well equipped for conducting organic synthetic reactions and subsequent purification and analysis procedures. We have the following chemical analysis capabilities: NMR, HPLC, GC-MS and LC-MS.

We obtain radionuclides from the Cyclotron Facility of PET Department, Warren Grant Magnuson Clinical Center and from commercial vendors. The Cyclotron Facility operates three cyclotrons with capabilities for producing several radioisotopes useful for PET. We currently utilize Fluorine-18, Copper-64, Yttrium-86, Zirconium-89 and Bromine-76. Gallium-68 is obtained from Ge-68/Ga-68 generator.

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Staff

Dale O. Kiesewetter, Ph.D.
Group Leader, PET/Optical Imaging Probe Section
Telephone: 301-451-3531

Ying Ma, Ph.D.
Staff Scientist
Telephone: 301-451-3534

Lixin Lang, Ph.D.
Chemist
Telephone: 301-451-3532

Ning Guo, B.S.
Predoctoral Visiting Fellow
Telephone: 301-594-0306

Xuyi Yue, Ph.D.
Visiting Fellow
Telephone: 301-452-2574

Xiaoxiang Zhang, Ph.D.
NIH/NIST Fellow
Telephone: 301-594-0310

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