Chemistry Weekly Seminar - Shvan Raheem, PhD Candidate

Title

Peptide-based Modular Linkers for Enhancing Radiopharmaceuticals

Abstract

Utilization of radiometallated peptides for both the detection and treatment of diseases such as infections and cancer has surged. Despite efforts from the research community, the high kidney uptake of most radiometallated peptides impedes the maximal potential of these radiopharmaceuticals and causes the radiometal to get residualized in the kidneys, which may induce kidney damage. In response to this, numerous methods have been employed to reduce the uptake of radiometallated-peptides in the kidneys, one of which is making chemical changes to the design of the linker to modulate polarity and/or charge of the whole radiometallated-peptide. Therefore, we have investigated the influence of net charge on the FDA-approved Tyr³-octreotate peptide “DOTA-TATE” using Ornithine and Glutamic acid as sources of positive and negative charges, respectively. We synthesized derivatives using manual solid-phase peptide synthesis methods including mechanical and ultrasonic agitation to effectively yield the gold standard DOTA-TATE and a series of derivatives (+2, +1, -1, -2), which were then radiolabeled with [⁶⁸Ga]Ga³⁺. Dynamic PET imaging and ex vivo biodistribution revealed a clear trend that positively charged derivatives had higher kidney uptakes whereas negatively charged derivatives had lower uptakes. With a better understanding of how drastic the changes to biological distribution of peptides can be when changing their net positive or negative charge, we sought to investigate the effects of a more unique charge distribution. We synthesized for the first time two novel unnatural amino acids bearing permanently zwitterionic moieties that are compatible with solid phase peptide synthesis. We incorporated these into a radiopharmaceutical peptide, and in comparison to the FDA approved [⁶⁸Ga]Ga-DOTA-TATE, our tracers [⁶⁸Ga]Ga-DOTA-Lys(Zw)_n-PEG₄-TATE and [⁶⁸Ga]Ga-DOTA-Pyr(Zw)-PEG₄-TATE showed faster clearance and lower uptake in kidneys and other healthy organs by 2-3 folds without impairing the tumor uptake. The presence of a permanently zwitterionic amino acid in peptides appears to dramatically change their biological distribution and provides improved pharmacokinetic behavior.

Date:    Friday, October 28

Time:    1:30 pm

Place:    ARTS 146