A Pretargeted Spect Imaging Strategy Employing Technetium-99M Based on Bioorthogonal Diels-Alder Click Chemistry

<p>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 <em>in vivo </em>“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 <em>in vivo</em> “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 <em>in vivo</em> “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.</p>

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Chemistry

Grantor

The Graduate School and University Center of The City University of New York

Year dc:date.available

2019

Author dc:creator

• Walsh, Justin H

Advisor dc:contributor.advisor

• Lynn Francesconi

Committee members dc:contributor.committeemember

• Brian Zeglis
• Jason Lewis
• Maria Contel

• Amino Acids, Peptides, and Proteins
• Inorganic Chemistry
• Medicinal-Pharmaceutical Chemistry
• Radiochemistry
• bioorthogonal
• pretargeting
• technetium
• rhenium
• imaging
• radiopharmaceuticals

Repository record dc:identifier

https://academicworks.cuny.edu/gc_etds/3240

OAI identifier oai:identifier

oai:academicworks.cuny.edu:gc_etds-4269