Reduction of Negative Charge in Mercaptoacetyl-Based Chelators Influences the Biodistribution of Prostate-Specific Membrane Antigen-Targeting Pseudopeptides Labeled with Technetium-99m

TL;DR

This paper explores how changing the charge of a chelator in a prostate cancer imaging tracer affects its distribution in the body.

Contribution

The study introduces new PSMA-targeting tracers with modified chelators to improve imaging and reduce kidney retention.

Findings

Reducing the negative charge of the chelator improved tracer clearance from normal organs.

Modified tracers showed efficient tumor targeting and better tumor-to-background ratios.

Tracer affinity was slightly reduced but pharmacokinetics improved in the gastrointestinal tract.

Abstract

Prostate cancer (PCa) is the most common cancer and the
second
leading cause of death among men worldwide. Significant progress has
been made in managing PCa by targeting the prostate-specific membrane
antigen (PSMA), which holds great promise for improving the accuracy
and effectiveness of diagnosis. Previously, we reported a high-affinity
glutamate–urea–lysine (EuK)-based PSMA-targeting tracer,
BQ0413, containing the maE3 chelator for labeling with
technetium-99m for single-photon emission tomography diagnostic imaging.
BQ0413 demonstrated efficient tumor targeting in PCa patients with
concomitant elevated activity retention in the kidneys, which is typical
for EuK-based PSMA-targeting tracers. We hypothesized that a decrease
in the tracer’s total negative charge, by substituting negatively
charged glutamate residues in the maE3 chelator with polar
neutral serine, could decrease activity retention in the kidneys.
The present study aimed to evaluate the tumor targeting and biodistribution
profile of two new PSMA-targeting tracers, BQ0500 (maESE) and BQ0501
(maS3), in comparison to BQ0413 (maE3). Conjugates
were successfully radiolabeled with technetium-99m and characterized
in vitro and in vivo. [99mTc]­Tc-BQ0500 and [99mTc]­Tc-BQ0501 demonstrated PSMA-specific binding to PC3-pip cells
with picomolar affinity; however, the affinity was 3–5-fold
compromised in comparison with the reference [99mTc]­Tc-BQ0413.
Full replacement of glutamate residues by serines in [99mTc]­Tc-BQ0501 resulted in an improved overall clearance from normal
organs with a moderately increased accumulation of activity in the
gastrointestinal tract. [99mTc]­Tc-BQ0501 demonstrated efficient
tumor targeting and improved tumor-to-background ratios. These results
suggest that chelator modifications, such as charge alteration, play
a critical role in improving tumor targeting and pharmacokinetics
for EuK-based PSMA-targeting tracers.

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