C-terminal-modified LY2510924: a versatile scaffold for targeting C-X-C chemokine receptor type 4
Kentaro Suzuki1,2, Takashi Ui3, Akio Nagano4
1RI Research Department, Research Division, FUJIFILM Toyama Chemical Co., Ltd., 453-1, Shimo-Okura, Matsuo-Machi, Sammu-City, Chiba, 289-1592, Japan. kentaro.a.suzuki@fujifilm.com.
Abstract:
C-X-C chemokine receptor type 4 (CXCR4) constitutes a promising target for tumor diagnosis and therapy. Herein, we evaluate a new 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CXCR4 antagonist derived from LY2510924, FRM001, and its metal complexes as CXCR4-targeting probes. FRM001 was synthesized by modifying the C-terminus of LY2510924 with maleimido-mono-amide-DOTA via a cysteine linker. FRM001 exhibited CXCR4-specific binding with an affinity similar to that of the parental LY2510924. The binding affinity of FRM001 remained unchanged after complexation with Ga, Lu, and Y. The internalization of 67Ga-FRM001 into the cells was hardly observed. In mice biodistribution studies, 67Ga-FRM001 exhibited high accumulation in the tumor and the liver with rapid elimination rates from the blood. The hepatic accumulation of 67Ga-FRM001 was preferentially and significantly reduced by co-injecting a CXCR4 antagonist, AMD3100. The C-terminal-modified LY2510924 would constitute a versatile scaffold to develop CXCR4-targeting probes or therapeutics for tumor imaging or therapy.
Insights
A novel C-X-C chemokine receptor type 4 (CXCR4) antagonist, FRM001, shows specific binding and tumor accumulation. This modified LY2510924 derivative is a versatile scaffold for CXCR4-targeting probes in cancer imaging and therapy.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- C-X-C chemokine receptor type 4 (CXCR4) is a key target for cancer diagnosis and treatment.
- LY2510924 is a known CXCR4 antagonist.
Purpose of the Study:
- To evaluate a new 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CXCR4 antagonist, FRM001, derived from LY2510924.
- To assess FRM001 and its metal complexes as CXCR4-targeting probes for tumor imaging and therapy.
Main Methods:
- FRM001 synthesized by conjugating DOTA to LY2510924 via a cysteine linker.
- CXCR4 binding affinity and metal complexation (Ga, Lu, Y) evaluated.
- Cellular internalization and biodistribution studies in mice using 67Ga-FRM001.
Main Results:
- FRM001 demonstrated CXCR4-specific binding with affinity comparable to LY2510924.
- Binding affinity was maintained after complexation with Ga, Lu, and Y.
- 67Ga-FRM001 showed high tumor and liver accumulation with rapid blood clearance in mice.
- Hepatic accumulation was reduced by co-injecting AMD3100.
Conclusions:
- C-terminal modification of LY2510924 yields FRM001, a versatile scaffold for developing CXCR4-targeting probes.
- FRM001 and its metal complexes show potential for tumor imaging and therapy targeting CXCR4.
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