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Novel ¹⁷⁷Lu-Labeled [Thz¹⁴]Bombesin(6-14) Derivatives with Low Pancreas Accumulation for Targeting Gastrin-Releasing

Lei Wang¹, Devon E Chapple¹, Hsiou-Ting Kuo¹

¹Department of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada.

Pharmaceuticals (Basel, Switzerland)

|April 26, 2025

Abstract:

Background/Objectives: Gastrin-releasing peptide receptor is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake of reported GRPR-targeted radioligands limits their clinical applications. Our group previously reported one ⁶⁸Ga-labeled GRPR antagonist, [⁶⁸Ga]Ga-TacsBOMB5 (⁶⁸Ga-DOTA-Pip-[D-Phe⁶,NMe-Gly¹¹,Leu¹³ψThz¹⁴]Bombesin(6-14)), and two agonists, [⁶⁸Ga]Ga-LW01110 (⁶⁸Ga-DOTA-Pip-[D-Phe⁶,Tle¹⁰,NMe-His¹²,Thz¹⁴]Bombesin(6-14)) and [⁶⁸Ga]Ga-LW01142 (⁶⁸Ga-DOTA-Pip-[D-Phe⁶,His⁷,Tle¹⁰,NMe-His¹²,Thz¹⁴]Bombesin(6-14)) showing minimal pancreas uptake. Thus, in this study, we prepared their ¹⁷⁷Lu-labeled analogs, evaluated their therapeutic potentials, and compared them with the clinically evaluated [¹⁷⁷Lu]Lu-AMBA. Methods: GRPR binding affinities were determined by in vitro competition binding assay using PC-3 prostate cancer cells. Longitudinal SPECT/CT imaging and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice. Dosimetry data were calculated from the biodistribution results. Results: The K_i(GRPR) values of Lu-TacsBOMB5, Lu-LW01110, Lu-LW01142, and Lu-AMBA were 12.6 ± 1.02, 3.07 ± 0.15, 2.37 ± 0.28, and 0.33 ± 0.16 nM, respectively. SPECT/CT images and biodistribution results demonstrated good tumor accumulation of [¹⁷⁷Lu]Lu-TacsBOMB5, [¹⁷⁷Lu]Lu-LW01110, and [¹⁷⁷Lu]Lu-LW01142 at early time points with rapid clearance over time. The pancreas uptake of all three [Thz¹⁴]Bombesin(6-14)-derived ligands was significantly lower than that of [¹⁷⁷Lu]Lu-AMBA at all time points. The calculated absorbed doses of [¹⁷⁷Lu]Lu-TacsBOMB5, [¹⁷⁷Lu]Lu-LW01110, and [¹⁷⁷Lu]Lu-LW01142 in PC-3 tumor xenografts were 87.1, 312, and 312 mGy/MBq, respectively, higher than that of [¹⁷⁷Lu]Lu-AMBA (79.1 mGy/MBq), but lower than that of the previously reported [¹⁷⁷Lu]Lu-RM2 (429 mGy/MBq). Conclusions: Our data suggest that [¹⁷⁷Lu]Lu-TacsBOMB5 and [¹⁷⁷Lu]Lu-LW01142 reduce radiation exposure to the pancreas. However, further optimizations are needed for both radioligands to prolong their tumor retention and enhance treatment efficacy.

Insights

New radioligands targeting the gastrin-releasing peptide receptor (GRPR) show reduced pancreas uptake for improved cancer therapy. [177Lu]Lu-TacsBOMB5 and [177Lu]Lu-LW01142 offer lower radiation exposure to the pancreas, though further optimization is needed for enhanced tumor retention.

Area of Science:

Nuclear Medicine
Radiopharmaceutical Chemistry
Oncology

Background:

Gastrin-releasing peptide receptor (GRPR) is a key target for cancer diagnosis and therapy.
High pancreas uptake of existing GRPR-targeted radioligands limits clinical use.
Previous work identified 68Ga-labeled GRPR antagonists and agonists with low pancreas uptake.

Purpose of the Study:

To prepare and evaluate 177Lu-labeled analogs of previously identified GRPR-targeting radioligands.
To assess their therapeutic potential and compare them with the clinically used 177Lu-AMBA.
To investigate their tumor accumulation, biodistribution, and dosimetry in a preclinical model.

Main Methods:

In vitro competition binding assays using PC-3 prostate cancer cells to determine GRPR binding affinities (Ki).
Longitudinal SPECT/CT imaging in PC-3 tumor-bearing mice.
Ex vivo biodistribution studies and dosimetry calculations based on observed uptake.

Main Results:

The Ki values for Lu-TacsBOMB5, Lu-LW01110, Lu-LW01142, and Lu-AMBA were determined.
SPECT/CT and biodistribution showed good tumor accumulation and rapid clearance for the new 177Lu-labeled ligands.
Pancreas uptake was significantly lower for all three new ligands compared to Lu-AMBA.
Absorbed doses in tumors were comparable or higher than Lu-AMBA but lower than Lu-RM2.

Conclusions:

177Lu-labeled TacsBOMB5 and LW01142 demonstrate reduced radiation exposure to the pancreas.
These ligands show potential for GRPR-targeted cancer therapy with improved safety profiles.
Further optimization is required to enhance tumor retention and therapeutic efficacy.

Read full analysis

Keywords:

dosimetry gastrin-releasing peptide receptor lutetium-177 radioligand therapy single-photon emission computed tomography

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