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Identifying Potential Off-Target Protein Binders of Glutamate-Ureido-Lysine, a Prostate Cancer Specific Imaging Agent

revised on 08.10.2020, 13:04 and posted on 08.10.2020, 13:16 by Martin Bakht, John Hayward, Farsheed Shahbazi-Raz, Daniel Meister, Adam Pillon, Mathew Stover, Adam Tronchin, Lavleen Mader, Bre-Anne Fifield, Sheng-Yu Ku, Gi Jeong Cheon, Keon Wook Kang, Yuzhuo Wang, Xuesen Dong, Himisha Beltran, Lisa Porter, John F. Trant

Prostate-specific membrane antigen (PSMA) is highly overexpressed in most prostate cancers and is clinically visualized using PSMA-specific probes incorporating Glutamate-Ureido-Lysine (GUL). PSMA is effectively absent from certain high-mortality, treatment-resistant subsets of prostate cancers, such as neuroendocrine prostate cancer (NEPC); however, GUL-based probes still sometimes identify NEPC metastatic tumours. These probes may bind unknown proteins associated with PSMA-suppressed cancers. We identified the upregulation of PSMA-like aminopeptidase NAALADaseL and the metabotropic glutamate receptors (mGluRs) in NEPC; we found that the expression levels inversely correlate with PSMA expression and are associated with poor clinical prognosis indicating they may participate in NEPC disease progression. Computationally predicting that GUL-based probes bind well to these targets, we designed and synthesized a new fluorescent probe to investigate these proteins in vitro, where it shows excellent affinity for PSMA, NAALADaseL and specific mGluRs associated with poor prognosis.


CIHR 142189 (LAP)

NSERC 2018-06338 (JFT)

Ontario Early Researcher JFT-2019 (JFT)

Windsor Cancer Centre Foundation 2017-003 (JFT)

Prostate Cancer Fight Foundation (LAP)

Ontario Trillium Scholarship (MKB)

Banting Research Foundation (JFT)

Compute Canada (JFT)


Email Address of Submitting Author


University of Windsor



ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare no conflicts of interest.

Version Notes

V 1.1 October 7, 2020