Date of Degree

5-2019

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Lynn Francesconi

Committee Members

Brian Zeglis

Jason Lewis

Maria Contel

Subject Categories

Amino Acids, Peptides, and Proteins | Inorganic Chemistry | Medicinal-Pharmaceutical Chemistry | Radiochemistry

Keywords

bioorthogonal, pretargeting, technetium, rhenium, imaging, radiopharmaceuticals

Abstract

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, and 99mTc-SK(PEG5-Tz)C. Log P values were obtained to determine hydrophilicity of each complex. Bovine serum albumin (BSA) was modified with TCO, reacted with each complex, and the “click” reaction was confirmed using Radio-TLC. Biodistributions and blood half-life studies were then performed on healthy athymic mice to determine which complex exhibited the optimal excretory characteristics. The Radio-TLC results indicate that each complex contains a viable Tz moeity. The biodistribution results suggest that 99mTc-FK(PEG5-Tz)CR has the most promising excretory pathway wherein excretion through the gut and intestines is minimized. The blood half-life values obtained indicated that clearance from the blood is not likely too fast to prevent the in vivo “click” reaction from occurring. Mice bearing xenografted SW1222 tumors were pretargeted with A33-TCO followed by the 99mTc-peptide-Tz complexes. SPECT/CT images were obtained and the in vivo “click” was confirmed for both 99mTc-FK(Tz)C and 99mTc-FK(PEG5-Tz)CR. 99mTc-FK(PEG5-Tz)CR exhibited higher tumor:background ratios than did 99mTc-FK(Tz)C but had too high intestinal uptake for translation to the clinic.

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