Abstract
Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [68Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of 68Ga. We screened a library of >200 fluorine-containing structural derivatives of AMD-3465 to identify promising candidates for in vivo imaging of CXCR4 expression by positron emission tomography (PET). Compounds containing fluoroethyltriazoles consistently achieved higher docking scores. Six of these higher scoring compounds were radiolabeled by click chemistry and evaluated in PC3-CXCR4 cells and BALB/c mice bearing bilateral PC3-WT and PC3-CXCR4 xenograft tumors. The apparent CXCR4 affinity of the ligands was relatively low, but tumor uptake was CXCR4-specific. The tumor uptake of [18F]RPS-534 (7.2 ± 0.3 %ID/g) and [18F]RPS-547 (3.1 ± 0.5 %ID/g) at 1 h p.i. was highest, leading to high tumor-to-blood, tumor-to-muscle, and tumor-to-lung ratios. Total cell-associated activity better predicted in vivo tumor uptake than did the docking score or apparent CXCR4 affinity. By this metric, and on the basis of their high yielding radiosynthesis, high tumor uptake, and good contrast to background, [18F]RPS-547, and especially [18F]RPS-534, are promising 18F-labeled candidates for imaging CXCR4 expression.
Highlights
The transmembrane G-protein coupled receptor C-X-C chemokine receptor type 4 (CXCR4), which binds to the chemokine CXCL12, is expressed on many cell types, including various types of cancer cells
CXCR4 plays a key role in organ-specific metastasis, directing
We present a novel series of [18 F]fluoroethyltriazolyl-containing monocyclam derivatives and highlight in particular [18 F]RPS-534 and [18 F]RPS-547, which demonstrate improved CXCR4-dependent tumor uptake and tumor-to-background ratios over [18 F]RPS-544
Summary
The transmembrane G-protein coupled receptor C-X-C chemokine receptor type 4 (CXCR4), which binds to the chemokine CXCL12, is expressed on many cell types, including various types of cancer cells. Activation of CXCR4 by its natural ligand stromal cell-derived factor 1 (SDF-1). Molecules 2019, 24, 1612 the migration of malignant cells expressing this receptor toward microenvironments where the cognate ligand is secreted [4,5,6,7,8,9,10]. There is no clinically approved imaging agent to assess CXCR4 expression in patients. The radiotracer, [68 Ga]Pentixafor, a cyclic pentapeptide incorporating the chelate, DOTA, is under clinical investigation for imaging CXCR4 expression in Europe [11,12,13,14,15,16,17,18]. As 68 Ga is obtained from the 68 Ge/68 Ga generator the maximum produced activity of 68 Ga is typically low (1.85 GBq) [19] precluding large-scale production for regional distribution
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