Development of an Optimized CXCR4-Targeting Theranostic Pair

Area of Science:

• Nuclear Medicine
• Radiopharmaceutical Chemistry
• Oncology

Background:

• C-X-C chemokine receptor 4 (CXCR4) is a target in various cancers.
• LY2510924 is a known CXCR4-targeting peptide.
• Development of novel radiolabeled peptides for improved targeting and theranostic applications is ongoing.

Purpose of the Study:

• To develop and evaluate a new CXCR4-targeting radiolabeled peptide, BL34, for potential use as a radiotheranostic agent.
• To assess the imaging and therapeutic efficacy of BL34 in preclinical mantle cell lymphoma models.

Main Methods:

• Structure-activity relationship studies were used to design a novel cyclic peptide, BL34, with enhanced CXCR4 binding.
• BL34 was radiolabeled with Gallium-68 ([⁶⁸Ga]Ga) for PET imaging and Lutetium-177 ([¹⁷⁷Lu]Lu) for SPECT imaging and therapy.
• In vivo studies were conducted in mice bearing mantle cell lymphoma xenografts, including PET/SPECT imaging, biodistribution, and therapeutic efficacy assessments.

Main Results:

• The optimized cyclic peptide BL34 exhibited a 3-fold improvement in CXCR4 binding compared to LY2510924.
• [⁶⁸Ga]Ga-BL34 demonstrated high tumor contrast and specific uptake in preclinical imaging.
• [¹⁷⁷Lu]Lu-BL34 showed favorable biodistribution with high tumor uptake and rapid renal excretion, leading to a dose-dependent survival benefit in therapeutic studies.

Conclusions:

• BL34 represents a novel CXCR4-targeting pharmacophore with excellent imaging and therapeutic properties.
• [⁶⁸Ga]Ga-BL34 and [¹⁷⁷Lu]Lu-BL34 are promising candidates for clinical translation as radiotheranostic agents for CXCR4-expressing cancers.