Physical Sciences and Mathematics Commons^™

A Pretargeted Spect Imaging Strategy Employing Technetium-99m Based On Bioorthogonal Diels-Alder Click Chemistry, Justin H. Walsh

Dissertations, Theses, and Capstone Projects

A series of related N₃S ^99mTc-peptide complexes were synthesized and tested for use in pretargeting SPECT imaging that utilizes the bioorthogonal Diels-Alder click reaction between tetrazine (Tz) and transcyclooctene (TCO). The objective was to optimize the excretory pathways of the ^99mTc-peptide complexes for maximum tumor targeting with the in vivo “click” and minimum non-target uptake. The ^99mTc–tetrazine constructs were prepared by reaction of ^99mTc-peptide complexes (^99mTc-FKC, ^99mTc-FKCR, ^99mTc-DKC, and ^99mTc-SKC) with Tz-NHS or Tz-PEG₅-NHS to form ^99mTc FK(Tz)C, ^99mTc-FK(PEG₅-Tz)CR, ^99mTc-DK(PEG₅-Tz)C, …

Pretargeted Radioimmunotherapy Utilizing The Inverse Electron Demand Diels-Alder Reaction, Rosemery Membreno

Dissertations, Theses, and Capstone Projects

Radioimmunotherapy capitalizes on the specificity and affinity of antibodies for their antigens to localize radioactivity at the tumor site. One limitation in using antibodies is their long circulation time, which can take days to weeks to fully clear from blood circulation. When a radioisotope is directly conjugated to this immunoglobulin vector, the red marrow and other healthy organs are receiving a constant radiation dose while it is in blood circulation. This not only harms healthy organs, but limits the dose of radioactivity that can be administered thus prolonging treatment. A promising alternative to limit the radiation dose to non-tumor tissue …

The Development Of Novel Platforms For The Imaging Of Cancer By Positron Emission Tomography, Brendon E. Cook

Dissertations, Theses, and Capstone Projects

The role of antibody-based imaging of cancer by positron emission tomography (PET) has expanded significantly in recent years and is poised to radically alter the way that cancer is diagnosed and treated. However, one hurdle that remains is the potentially harmful radiation dose that comes from these imaging agents, as the long circulation time of antibodies (days to weeks) necessitates the use of radionuclides with comparable physical half-lives (i.e. ⁸⁹Zr, ¹²⁴I, etc.). One particularly promising solution is the use of the inverse electron demand Diels-Alder (IEDDA) reaction between a 1,2,4,5-tetrazine (Tz) and a trans-cyclooctene (TCO) for pretargeting. …

Pretargeting Of Internalizing Trastuzumab And Cetuximab With A 18f-Tetrazine Tracer In Xenograft Models, Outi Keinänen, Kimberly Fung, Jacob Pourat, Vilma Jallinoja, Delphine Vivier, Nagavara Kishore Pillarsetty, Anu J. Airaksinen, Jason S. Lewis, Brian M. Zeglis, Mirkka Sarparanta

Publications and Research

Background: Pretargeting-based approaches are being investigated for radioimmunoimaging and therapy applications to reduce the effective radiation burden to the patient. To date, only a few studies have used short-lived radioisotopes for pretargeting of antibodies, and such examples with internalizing antibodies are even rarer. Herein, we have investigated pretargeting methodology using inverse electron-demand Diels-Alder (IEDDA) for tracing two clinically relevant, internalizing monoclonal antibodies, cetuximab and trastuzumab.

Results: Bioorthogonal reaction between tetrazine and trans-cyclooctene (TCO) was used for tracing cetuximab and trastuzumab in vivo with a fluorine-18 (t½ = 109.8 min) labelled tracer. TCO-cetuximab or TCO-trastuzumab was administered 24, 48, or 72 …