What does this research mean for the field?

The negatively charged aspartic acid linker significantly enhances the tumor-targeting properties and biodistribution of [177Lu]Lu-DOTA-Lys(Asp-p-TBA)-GGNle-CycMSHhex compared to other linkers. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The study examines how negatively charged amino acid linkers impact the tumor-targeting properties of specific radiolabeled peptides.

February 26, 2026

Effect of a Negatively Charged Amino Acid Linker on the Tumor-Targeting Properties of 177 LuLu-Labeled 4- p -(Tolyl)butyric Acid-Conjugated Alpha-Melanocyte-Stimulating Hormone Peptides

Key Points

The study examines how negatively charged amino acid linkers impact the tumor-targeting properties of specific radiolabeled peptides.
Synthesis of DOTA-Lys-p-TBA-conjugated peptides using Fmoc chemistry
Measured MC1R binding affinities in B16/F10 melanoma cells
Biodistribution assessment of radiolabeled peptides in melanoma-bearing mice
Visualization of melanoma lesions using SPECT/CT imaging
DOTA-Lys(Asp-p-TBA)-GGNle-CycMSHhex had the highest IC50 value at 0.03 ± 0.03 nM
At 2 h postinjection, the tumor/kidney and tumor/liver uptake ratios were highest for DOTA-Lys(Asp-p-TBA)-GGNle-CycMSHhex
B16/F10 melanoma uptake peaked at 45.24 ± 1.72%ID/g at 2 h postinjection
Clear visualization of melanoma lesions was achieved using SPECT/CT at 2 h postinjection

Abstract

This study aimed to examine how negatively charged amino acid linkers influence the tumor-targeting and biodistribution properties of 177LuLu-labeled 4-p- (tolyl) butyric acid (p-TBA) -conjugated alpha-melanocyte-stimulating hormone peptides. The p-TBA moiety functions as an albumin binder (ALB), either directly attached to the peptide or through a negatively charged aspartic acid (Asp) or glutamic acid (Glu) linker. DOTA-Lys (p-TBA) -GGNle-CycMSHhex 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid-Lys (4-p- (tolyl) butyric acid) -GlyGly-Nle-cAsp-His-DPhe-Arg-Trp-Lys-CONH2, DOTA-Lys (Asp-p-TBA) -GGNle-CycMSHhex, and DOTA-Lys (Glu-p-TBA) -GGNle-CycMSHhex were synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry. Their melanocortin-1 receptor (MC1R) binding affinities were measured in B16/F10 melanoma cells, and the biodistribution of 177LuLu-labeled peptides was examined in B16/F10 melanoma-bearing mice at 0. 5, 2, 4, and 24 h postinjection. Additionally, the melanoma imaging capability of 177LuLu-DOTA-Lys (Asp-p-TBA) -GGNle-CycMSHhex was examined in B16/F10 melanoma-bearing mice. The IC50 values were 0. 5 ± 0. 09 (p-TBA), 0. 03 ± 0. 03 (Asp-p-TBA), and 7. 2 ± 0. 07 nM (Glu-p-TBA). Among the three, 177LuLu-DOTA-Lys (Asp-p-TBA) -GGNle-CycMSHhex displayed the highest tumor/kidney and tumor/liver uptake ratios at 2 and 4 h postinjection. The B16/F10 melanoma uptake of 177LuLu-DOTA-Lys (Asp-p-TBA) -GGNle-CycMSHhex was 20. 40 ± 1. 91, 45. 24 ± 1. 72, 31. 30 ± 2. 85, and 11. 16 ± 1. 79%ID/g at 0. 5, 2, 4, and 24 h postinjection, respectively. The B16/F10 melanoma lesions were clearly visualized by SPECT/CT using 177LuLu-DOTA-Lys (Asp-p-TBA) -GGNle-CycMSHhex as an imaging probe at 2 h postinjection. Overall, the presence and charge of the linker significantly affected MC1R binding and tumor uptake. The linker charge played a key role in the liver and kidney uptake of 177LuLu-DOTA-Lys (Asp-p-TBA) -GGNle-CycMSHhex and 177LuLu-DOTA-Lys (Glu-p-TBA) -GGNle-CycMSHhex. 177LuLu-DOTA-Lys (Asp-p-TBA) -GGNle-CycMSHhex exhibited the highest tumor/liver and tumor/kidney uptake ratios among the three 177LuLu-peptides, highlighting its potential for future melanoma therapy.

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Effect of a Negatively Charged Amino Acid Linker on the Tumor-Targeting Properties of 177 LuLu-Labeled 4- p -(Tolyl)butyric Acid-Conjugated Alpha-Melanocyte-Stimulating Hormone Peptides

Key Points

Abstract

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