A new class of PentixaFor- and PentixaTher-based theranostic agents with enhanced CXCR4-targeting efficiency.


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A new class of PentixaFor- and PentixaTher-based theranostic agents with enhanced CXCR4-targeting efficiency.
Osl T., Schmidt A., Schwaiger M., Schottelius M., Wester H.J.
1838-7640 (Electronic)
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Publication types: Journal Article
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Non-invasive PET imaging of CXCR4 expression in cancer and inflammation as well as CXCR4-targeted radioligand therapy (RLT) have recently found their way into clinical research by the development of the theranostic agents [ <sup>68</sup> Ga]PentixaFor (cyclo(D-Tyr <sup>1</sup> -D-[NMe]Orn <sup>2</sup> (AMBS-[ <sup>68</sup> Ga]DOTA)-Arg <sup>3</sup> -Nal <sup>4</sup> -Gly <sup>5</sup> ) = [ <sup>68</sup> Ga]DOTA-AMBS-CPCR4) and [ <sup>177</sup> Lu/ <sup>90</sup> Y]PentixaTher (cyclo(D-3-iodo-Tyr <sup>1</sup> -D-[NMe]Orn <sup>2</sup> (AMBS-[ <sup>177</sup> Lu/ <sup>90</sup> Y]DOTA)-Arg <sup>3</sup> -Nal <sup>4</sup> -Gly <sup>5</sup> ) = [ <sup>177</sup> Lu/ <sup>90</sup> Y]DOTA-AMBS-iodoCPCR4). Although convincing clinical results have already been obtained with both agents, this study was designed to further investigate the required structural elements for improved ligand-receptor interaction for both peptide cores (CPCR4 and iodoCPCR4). To this aim, a series of DOTA-conjugated CPCR4- and iodoCPCR4-based ligands with new linker structures, replacing the AMBA-linker in PentixaFor and PentixaTher, were synthesized and evaluated. Methods: The in vitro investigation of the novel compounds alongside with the reference peptides PentixaFor and PentixaTher encompassed the determination of hCXCR4 and mCXCR4 affinity (IC <sub>50</sub> ) of the respective <sup>nat</sup> Ga-, <sup>nat</sup> Lu-, <sup>nat</sup> Y- and <sup>nat</sup> Bi-complexes in Jurkat and Eμ-myc 1080 cells using [ <sup>125</sup> I]FC-131 and [ <sup>125</sup> I]CPCR4.3 as radioligands, respectively, as well as the evaluation of the internalization and externalization kinetics of selected <sup>68</sup> Ga- and <sup>177</sup> Lu-labeled compounds in hCXCR4-transfected Chem-1 cells. Comparative small animal PET imaging studies (1h p.i.) as well as in vivo biodistribution studies (1, 6 and 48h p.i.) were performed in Daudi (human B cell lymphoma) xenograft bearing CB17 SCID mice. Results: Based on the affinity data and cellular uptake studies, [ <sup>68</sup> Ga/ <sup>177</sup> Lu]DOTA-r-a-ABA-CPCR4 and [ <sup>68</sup> Ga/ <sup>177</sup> Lu]DOTA-r-a-ABA-iodoCPCR4 (with r-a-ABA = D-Arg-D-Ala-4-aminobenzoyl-) were selected for further evaluation. Both analogs show app. 10-fold enhanced hCXCR4 affinity compared to the respective references [ <sup>68</sup> Ga]PentixaFor and [ <sup>177</sup> Lu]PentixaTher, four times higher cellular uptake in hCXCR4 expressing cells and improved cellular retention. Unfortunately, the improved in vitro binding and uptake characteristics of [ <sup>68</sup> Ga]DOTA-r-a-ABA-CPCR4 and -iodoCPCR4 could not be recapitulated in initial PET imaging studies; both compounds showed similar uptake in the Daudi xenografts as [ <sup>68</sup> Ga]PentixaFor, alongside with higher background accumulation, especially in the kidneys. However, the subsequent biodistribution studies performed for the corresponding <sup>177</sup> Lu-labeled analogs revealed a clear superiority of [ <sup>177</sup> Lu]DOTA-r-a-ABA-CPCR4 and [ <sup>177</sup> Lu]DOTA-r-a-ABA-iodoCPCR4 over [ <sup>177</sup> Lu]PentixaTher with respect to tumor uptake (18.3±3.7 and 17.2±2.0 %iD/g, respectively, at 1h p.i. vs 12.4±3.7%iD/g for [ <sup>177</sup> Lu]PentixaTher) as well as activity retention in tumor up to 48h. Especially for [ <sup>177</sup> Lu]DOTA-r-a-ABA-CPCR4 with its low background accumulation, tumor/organ ratios at 48h were 2- to 4-fold higher than those obtained for [ <sup>177</sup> Lu]PentixaTher (except for kidney). Conclusions: The in-depth evaluation of a series of novel CPCR4- and iodoCPCR4 analogs with modified linker structure has yielded reliable structure-activity relationships. It was generally observed that a) AMBA-by-ABA-substitution leads to enhanced ligand internalization, b) the extension of the ABA-linker by two additional amino acids (DOTA-Xaa <sub>2</sub> -Xaa <sub>1</sub> -ABA-) provides sufficient linker length to minimize the interaction of the [M <sup>3+</sup> ]DOTA-chelate with the receptor, and that c) introduction of a cationic side chain (Xaa <sub>2</sub> ) greatly enhances receptor affinity of the constructs, obliterating the necessity for Tyr <sup>1</sup> -iodination of the pentapeptide core to maintain high receptor affinity (such as in [ <sup>177</sup> Lu]PentixaTher). As a result, [ <sup>177</sup> Lu]DOTA-r-a-ABA-CPCR4 has emerged from this study as a powerful second-generation therapeutic CXCR4 ligand with greatly improved targeting efficiency and tumor retention and will be further evaluated in preclinical and clinical CXCR4-targeted dosimetry and RLT studies.
CXCR4, PET, cancer, cyclic pentapeptide, radioligand therapy
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13/08/2020 9:27
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23/11/2022 8:08
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