Investigation of Radiolabeled KISS1R Ligands as Promising Tools for Diagnosis and Treatment of Triple-Negative Breast Cancer.

Taş H, Schäfer M, Shuja-Uddin A, Bauder-Wüst U, Kovacs Dos Santos L, Bartnitzky L, Oden F, Platzk M, König T, Rüther PL, Pook E, Dvořáková Bendová K and 4 more

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Nový Z, Petřík M, Hagemann UB, Benešová-Schäfer M

Molecular pharmaceutics3 Mar 2026

PMID41774810PMCIDPMC13058897DOI10.1021/acs.molpharmaceut.5c01853PepBankPUB-41774810

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Summary

Kisspeptins (KPs) and their receptor (KISS1R) promote metastasis and tumor progression in various cancers such as triple-negative breast cancer (TNBC). Targeting KISS1R holds great promise for molecular imaging and targeted radionuclide therapy of aggressively disseminated cancers. First ligand-based approaches using Ga-68/Lu-177-labeled KPs (KP-10, KP-54) have demonstrated feasibility but suffer from proteolytic degradation and low uptake in KISS1R positive tumors. However, lead structure optimization alone is insufficient, as KISS1R biology remains unexplored in a radiotheranostic context. In this study, N-terminally functionalized conjugates of KP-10, KP-54, and the hybrid peptide KiSS-34 (AMBA-2-Nal-Gly-Leu-Arg-Trp-NH₂), including scrambled controls, were synthesized in high purity (≥95%) for comparative studies. The conjugation to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and Alexa-Fluor-488 (AF-488) functionalities preserved biological activity, confirmed by (sub)nanomolar EC₅₀-values (0.05-0.85 nM) in calcium mobilization assays in transfected CHO-KISS1R cells. Conventional target detection methods using antibodies (Abs) and AF-488-KPs failed to visualize KISS1R in both model (CHO-KISS1R) and native cancer cell lines, likely due to unspecific Abs and rapid KISS1R internalization upon agonist stimulation. However, rapid KISS1R internalization was successfully visualized via live-cell imaging using AF-488-KP-10 and novel analogue AF-488-KiSS-34. Furthermore, DOTA-KPs were radiolabeled with Lu-177 in high efficiencies (≥95%) and examined in internalization assays, showing highest uptake (4.8%) and internalization rate (45.9%) for [¹⁷⁷Lu]Lu-DOTA-KiSS-34 in CHO-KISS1R cells compared to its KP-10 analogue (total uptake: 1.3%; internalization rate: 37.6%). Higher uptakes likely derive from faster binding kinetics, improved KISS1R targeting, and/or slower dissociation as evidenced by oil-based kinetics assays showing higher total uptake for [¹⁷⁷Lu]Lu-DOTA-KiSS-34 (15.3%) compared to KP-10 (3.8%) and KP-54 (4.5%) counterparts after 30 min. Positron emission tomography/computerized tomography (PET/CT) imaging, urine analysis, and all in vitro studies indicate that Ga-68/Lu-177-labeled DOTA-KiSS-34 exhibits superior pharmacodynamics, pharmacokinetics, and in vivo stability compared to its KP-10 and KP-54 analogues, which are critically suffering from rapid in vivo degradation. These results position DOTA-KiSS-34 as a strong structural lead for KISS1R-based radiotheranostics. Nevertheless, the dynamics between KPs and KISS1R need to be further investigated to fully harness the radiotheranostic potential of KISS1R for TNBC and other cancers.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study7

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone7

In this study, Kisspeptin-10 was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Kisspeptin-10.

01AnimalNot a test of Kisspeptin-10 aloneAnimal study (in vivo)Pharmacokinetics
Ga-68/Lu-177-labeled DOTA-KiSS-34 showed superior pharmacodynamics, pharmacokinetics and in vivo stability than its KP-10 and KP-54 analogues, which suffer rapid in vivo degradation.
In plain wordsIn imaging studies, labelled KP-10 conjugates broke down quickly in the body and performed worse than the labelled KiSS-34 conjugate.
Peptide
Kisspeptin-10
Outcome
DecreaseIn vivo stability and pharmacokinetics of labeled KP-10 analogues
Study
n: not reported in source
PET/CT imaging and urine analysis
Comparator
DOTA-KiSS-34
Outcome group
Pharmacokinetics · Pharmacology
Source sentences
Summary
Positron emission tomography/computerized tomography (PET/CT) imaging, urine analysis, and all in vitro studies indicate that Ga-68/Lu-177-labeled DOTA-KiSS-34 exhibits superior pharmacodynamics, pharmacokinetics, and in vivo stability compared to its KP-10 and KP-54 analogues, which are critically suffering from rapid in vivo degradation.
In this study, Kisspeptin-10 was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-10.
Show in the study text Report a problemFND-4177481007
02LabNot a test of Kisspeptin-10 aloneIn vitro (cells)Activity measurement
In transfected CHO-KISS1R cells, DOTA and Alexa-Fluor-488 conjugates of KP-10, KP-54 and KiSS-34 preserved biological activity, with EC50 values of 0.05-0.85 nM in calcium mobilization assays.
In plain wordsIn lab cells, peptide conjugates with a chelator or dye kept their activity at the KISS1 receptor.
Peptide
Kisspeptin-10
Outcome
Not applicableReceptor activation by conjugates (EC50)
Study
n: not reported in source
CHO-KISS1R cells
Outcome group
Receptor activity and mechanism · Cancer
Measurements
EC50
0.05 to 0.85 nM
conjugates, CHO-KISS1R cells
Source sentences
Summary
The conjugation to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and Alexa-Fluor-488 (AF-488) functionalities preserved biological activity, confirmed by (sub)nanomolar EC₅₀-values (0.05-0.85 nM) in calcium mobilization assays in transfected CHO-KISS1R cells.
In this study, Kisspeptin-10 was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-10.
Show in the study text Report a problemFND-4177481001
03LabNot a test of Kisspeptin-10 aloneIn vitro (cells)Activity measurement
In live-cell imaging, AF-488-KP-10 visualized rapid KISS1R internalization.
In plain wordsIn lab cells, a dye-labelled KP-10 conjugate let researchers see the receptor being taken into the cell.
Peptide
Kisspeptin-10
Outcome
Not applicableVisualization of KISS1R internalization with AF-488-KP-10
Study
n: not reported in source
CHO-KISS1R cells
Outcome group
Receptor activity and mechanism · Cancer
Source sentences
Summary
However, rapid KISS1R internalization was successfully visualized via live-cell imaging using AF-488-KP-10 and novel analogue AF-488-KiSS-34.
In this study, Kisspeptin-10 was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-10.
Show in the study text Report a problemFND-4177481002
04LabNot a test of Kisspeptin-10 aloneIn vitro (cells)Activity measurement
In CHO-KISS1R cells, the Lu-177-labeled DOTA-KP-10 analogue had a total uptake of 1.3%, lower than 4.8% for [177Lu]Lu-DOTA-KiSS-34.
In plain wordsIn lab cells, a radiolabelled KP-10 conjugate was taken up less than the radiolabelled KiSS-34 conjugate.
Peptide
Kisspeptin-10
Outcome
DecreaseTotal uptake of Lu-177-DOTA-KP-10 analogue
Study
n: not reported in source
CHO-KISS1R cells
Comparator
[177Lu]Lu-DOTA-KiSS-34
Outcome group
Receptor activity and mechanism · Cancer
Measurements
Total uptake
1.3%
KP-10 analogue
Source sentences
Summary
Furthermore, DOTA-KPs were radiolabeled with Lu-177 in high efficiencies (≥95%) and examined in internalization assays, showing highest uptake (4.8%) and internalization rate (45.9%) for [¹⁷⁷Lu]Lu-DOTA-KiSS-34 in CHO-KISS1R cells compared to its KP-10 analogue (total uptake: 1.3%; internalization rate: 37.6%).
In this study, Kisspeptin-10 was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-10.
Show in the study text Report a problemFND-4177481003
05LabNot a test of Kisspeptin-10 aloneIn vitro (cells)Activity measurement
In CHO-KISS1R cells, the Lu-177-labeled DOTA-KP-10 analogue had an internalization rate of 37.6%, lower than 45.9% for [177Lu]Lu-DOTA-KiSS-34.
In plain wordsIn lab cells, a radiolabelled KP-10 conjugate entered cells less than the radiolabelled KiSS-34 conjugate.
Peptide
Kisspeptin-10
Outcome
DecreaseInternalization rate of Lu-177-DOTA-KP-10 analogue
Study
n: not reported in source
CHO-KISS1R cells
Comparator
[177Lu]Lu-DOTA-KiSS-34
Outcome group
Receptor activity and mechanism · Cancer
Measurements
Internalization rate
37.6%
KP-10 analogue
Source sentences
Summary
Furthermore, DOTA-KPs were radiolabeled with Lu-177 in high efficiencies (≥95%) and examined in internalization assays, showing highest uptake (4.8%) and internalization rate (45.9%) for [¹⁷⁷Lu]Lu-DOTA-KiSS-34 in CHO-KISS1R cells compared to its KP-10 analogue (total uptake: 1.3%; internalization rate: 37.6%).
In this study, Kisspeptin-10 was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-10.
Show in the study text Report a problemFND-4177481004
06LabNot a test of Kisspeptin-10 aloneIn vitro (cells)Activity measurement
In oil-based kinetics assays after 30 min, the Lu-177-labeled DOTA-KP-10 counterpart had a total uptake of 3.8%, lower than 15.3% for [177Lu]Lu-DOTA-KiSS-34.
In plain wordsIn lab cell assays, a radiolabelled KP-10 conjugate was taken up less after 30 minutes than the radiolabelled KiSS-34 conjugate.
Peptide
Kisspeptin-10
Outcome
DecreaseTotal uptake in oil-based kinetics assay at 30 min
Study
n: not reported in source
CHO-KISS1R cells
Comparator
[177Lu]Lu-DOTA-KiSS-34
Outcome group
Receptor activity and mechanism · Cancer
Measurements
Total uptake
3.8%
KP-10 counterpart, 30 min
Source sentences
Summary
Higher uptakes likely derive from faster binding kinetics, improved KISS1R targeting, and/or slower dissociation as evidenced by oil-based kinetics assays showing higher total uptake for [¹⁷⁷Lu]Lu-DOTA-KiSS-34 (15.3%) compared to KP-10 (3.8%) and KP-54 (4.5%) counterparts after 30 min.
In this study, Kisspeptin-10 was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-10.
Show in the study text Report a problemFND-4177481005
07LabNot a test of Kisspeptin-10 aloneIn vitro (cells)Activity measurement
Antibodies and AF-488-labeled kisspeptins, including AF-488-KP-10, failed to visualize KISS1R in model and native cancer cell lines.
In plain wordsIn lab cells, antibodies and dye-labelled kisspeptins did not make the receptor visible.
Peptide
Kisspeptin-10
Outcome
No significant changeDetection of KISS1R with AF-488-KPs and antibodies
Study
n: not reported in source
CHO-KISS1R cells
Outcome group
Receptor activity and mechanism · Cancer
Source sentences
Summary
Conventional target detection methods using antibodies (Abs) and AF-488-KPs failed to visualize KISS1R in both model (CHO-KISS1R) and native cancer cell lines, likely due to unspecific Abs and rapid KISS1R internalization upon agonist stimulation.
In this study, Kisspeptin-10 was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-10.
Show in the study text Report a problemFND-4177481006

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
10 Oct 2026, 09:43 UTC
Study results updated
Version 1
9 Oct 2026, 03:04 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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