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Side-Chain Modified [^99mTc]Tc-DT1 Mimics: A Comparative Study in NTS₁R-Positive Models.

Panagiotis Kanellopoulos¹, Berthold A Nock¹, Maritina Rouchota²

¹Molecular Radiopharmacy, INRaSTES, NCSR "Demokritos", 15341 Athens, Greece.

International Journal of Molecular Sciences

|November 14, 2023

Summary

New radiolabeled neurotensin analogs ([^99mTc]Tc-DT11 and [^99mTc]Tc-DT12) show improved stability and tumor uptake for neurotensin subtype 1 receptor (NTS₁R)-expressing cancers. [^99mTc]Tc-DT11 demonstrates promising theranostic potential for SPECT/CT imaging.

Keywords:

Tc-99m-radioligand angiotensin-converting enzyme diagnostic imaging lateral chain modification metabolic stability neprilysin neurotensin subtype 1 receptor peptidase inhibition radiolabeled neurotensin

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Area of Science:

Radiopharmaceutical chemistry
Molecular imaging
Oncology

Background:

Radiolabeled neurotensin analogs target neurotensin subtype 1 receptor (NTS₁R)-expressing cancers for theranostics.
Peptidase degradation by neprilysin (NEP) and angiotensin-converting enzyme (ACE) limits clinical success of these analogs.
Previous palmitoylation ([^99mTc]Tc-DT9) improved stability but caused unfavorable pharmacokinetics.

Purpose of the Study:

To develop novel [^99mTc]Tc-DT1 analogs with improved in vivo stability and pharmacokinetics for NTS₁R-positive cancer theranostics.
To evaluate the impact of different pendant groups on Lys⁷ on analog stability, receptor affinity, and tumor uptake.
To identify lead candidates for clinical validation in patients.

Main Methods:

Synthesis of three new [^99mTc]Tc-DT1 mimics ([^99mTc]Tc-DT10, [^99mTc]Tc-DT11, [^99mTc]Tc-DT12) with varying pendant groups at Lys⁷.
Assessment of receptor affinity and internalization in NTS₁R-positive cells.
Evaluation of in vivo stability and AsPC-1 tumor uptake in mice, with and without NEP/ACE inhibition, using SPECT/CT.

Main Results:

Longer chain modifications ([^99mTc]Tc-DT11 and [^99mTc]Tc-DT12) significantly enhanced in vivo stability compared to [^99mTc]Tc-DT1.
Tumor uptake was markedly improved for [^99mTc]Tc-DT11 and [^99mTc]Tc-DT12 compared to [^99mTc]Tc-DT1.
[^99mTc]Tc-DT11 exhibited the highest AsPC-1 tumor uptake and favorable pharmacokinetics, even without NEP inhibition.

Conclusions:

Modified [^99mTc]Tc-DT1 analogs, particularly [^99mTc]Tc-DT11, overcome peptidase degradation, leading to superior tumor targeting.
[^99mTc]Tc-DT11 shows significant potential as a theranostic agent for NTS₁R-positive cancers.
Further clinical validation of [^99mTc]Tc-DT11 for SPECT/CT imaging in patients is warranted.