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Published on: February 17, 2022
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.
Abstract:
Radiolabeled neurotensin analogs have been developed as candidates for theranostic use against neurotensin subtype 1 receptor (NTS1R)-expressing cancer. However, their fast degradation by two major peptidases, neprilysin (NEP) and angiotensin-converting enzyme (ACE), has hitherto limited clinical success. We have recently shown that palmitoylation at the ε-amine of Lys7 in [99mTc]Tc-[Lys7]DT1 (DT1, N4-Gly-Arg-Arg-Pro-Tyr-Ile-Leu-OH, N4 = 6-(carboxy)-1,4,8,11-tetraazaundecane) led to the fully stabilized [99mTc]Tc-DT9 analog, displaying high uptake in human pancreatic cancer AsPC-1 xenografts but unfavorable pharmacokinetics in mice. Aiming to improve the in vivo stability of [99mTc]Tc-DT1 without compromising pharmacokinetics, we now introduce three new [99mTc]Tc-DT1 mimics, carrying different pendant groups at the ε-amine of Lys7: MPBA (4-(4-methylphenyl)butyric acid)-[99mTc]Tc-DT10; MPBA via a PEG4-linker-[99mTc]Tc-DT11; or a hydrophilic PEG6 chain-[99mTc]Tc-DT12. The impact of these modifications on receptor affinity and internalization was studied in NTS1R-positive cells. The effects on stability and AsPC-1 tumor uptake were assessed in mice without or during NEP/ACE inhibition. Unlike [99mTc]Tc-DT10, the longer-chain modified [99mTc]Tc-DT11 and [99mTc]Tc-DT12 were significantly stabilized in vivo, resulting in markedly improved tumor uptake compared to [99mTc]Tc-DT1. [99mTc]Tc-DT11 was found to achieve the highest AsPC-1 tumor values and good pharmacokinetics, either without or during NEP inhibition, qualifying for further validation in patients with NTS1R-positive tumors using SPECT/CT.
Insights
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.
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.
