[99mTc]Tc-PentixaTec: development, extensive pre-clinical evaluation, and first human experience.
Details
Serval ID
serval:BIB_F01E355CA9DA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
[99mTc]Tc-PentixaTec: development, extensive pre-clinical evaluation, and first human experience.
Journal
European journal of nuclear medicine and molecular imaging
ISSN
1619-7089 (Electronic)
ISSN-L
1619-7070
Publication state
Published
Issued date
11/2023
Peer-reviewed
Oui
Volume
50
Number
13
Pages
3937-3948
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
The clinical success non-invasive imaging of CXCR4 expression using [ <sup>68</sup> Ga]Ga-PentixaFor-PET warrants an expansion of the targeting concept towards conventional scintigraphy/SPECT with their lower cost and general availability. To this aim, we developed and comparatively evaluated a series of <sup>99m</sup> Tc-labeled cyclic pentapeptides based on the PentixaFor scaffold.
Six mas <sub>3</sub> -conjugated CPCR4 analogs with different 4-aminobenzoic acid (Abz)-D-Ala-D-Arg-aa <sub>3</sub> linkers (L1-L6) as well as the corresponding HYNIC- and N <sub>4</sub> -analogs of L6-CPCR4 were synthesized via standard SPPS. Competitive binding studies (IC <sub>50</sub> and IC <sub>50</sub> inv) were carried out using Jurkat T cell lymphoma cells and [ <sup>125</sup> I]FC-131 as radioligand. Internalization kinetics were investigated using hCXCR4-overexpressing Chem-1 cells. Biodistribution studies and small animal SPECT/CT imaging (1 h p.i.) were carried out using Jurkat xenograft bearing CB17/SCID mice. Based on the preclinical results, [ <sup>99m</sup> Tc]Tc-N <sub>4</sub> -L6-CPCR4 ([ <sup>99m</sup> Tc]Tc-PentixaTec) was selected for an early translation to the human setting. Five patients with hematologic malignancies underwent [ <sup>99m</sup> Tc]Tc-N <sub>4</sub> -L6-CPCR4 SPECT/planar imaging with individual dosimetry.
Of the six mas <sub>3</sub> -conjugated peptides, mas <sub>3</sub> -L6-CPCR4 (mas <sub>3</sub> -dap-r-a-Abz-CPCR4) showed the highest CXCR4 affinity (IC <sub>50</sub> = 5.0 ± 1.3 nM). Conjugation with N <sub>4</sub> (N <sub>4</sub> -L6-CPCR4) further improved hCXCR4 affinity to 0.6 ± 0.1 nM. [ <sup>99m</sup> Tc]Tc-N <sub>4</sub> -L6-CPCR4 also showed the most efficient internalization (97% of total cellular activity at 2 h) and the highest tumor accumulation (8.6 ± 1.3% iD/g, 1 h p.i.) of the compounds investigated. Therefore, [ <sup>99m</sup> Tc]Tc-N <sub>4</sub> -L6-CPCR4 (termed [ <sup>99m</sup> Tc]Tc-PentixaTec) was selected for first-in-human application. [ <sup>99m</sup> Tc]Tc-PentixaTec was well tolerated, exhibits a favorable biodistribution and dosimetry profile (2.1-3.4 mSv per 500 MBq) and excellent tumor/background ratios in SPECT and planar imaging.
The successive optimization of the amino acid composition of the linker structure and the N-terminal <sup>99m</sup> Tc-labeling strategies (mas <sub>3</sub> vs HYNIC vs N <sub>4</sub> ) has provided [ <sup>99m</sup> Tc]Tc-PentixaTec as a novel, highly promising CXCR4-targeted SPECT agent for clinical application. With its excellent CXCR4 affinity, efficient internalization, high uptake in CXCR4-expressing tissues, suitable clearance/biodistribution characteristics, and favorable human dosimetry, it holds great potential for further clinical use.
Six mas <sub>3</sub> -conjugated CPCR4 analogs with different 4-aminobenzoic acid (Abz)-D-Ala-D-Arg-aa <sub>3</sub> linkers (L1-L6) as well as the corresponding HYNIC- and N <sub>4</sub> -analogs of L6-CPCR4 were synthesized via standard SPPS. Competitive binding studies (IC <sub>50</sub> and IC <sub>50</sub> inv) were carried out using Jurkat T cell lymphoma cells and [ <sup>125</sup> I]FC-131 as radioligand. Internalization kinetics were investigated using hCXCR4-overexpressing Chem-1 cells. Biodistribution studies and small animal SPECT/CT imaging (1 h p.i.) were carried out using Jurkat xenograft bearing CB17/SCID mice. Based on the preclinical results, [ <sup>99m</sup> Tc]Tc-N <sub>4</sub> -L6-CPCR4 ([ <sup>99m</sup> Tc]Tc-PentixaTec) was selected for an early translation to the human setting. Five patients with hematologic malignancies underwent [ <sup>99m</sup> Tc]Tc-N <sub>4</sub> -L6-CPCR4 SPECT/planar imaging with individual dosimetry.
Of the six mas <sub>3</sub> -conjugated peptides, mas <sub>3</sub> -L6-CPCR4 (mas <sub>3</sub> -dap-r-a-Abz-CPCR4) showed the highest CXCR4 affinity (IC <sub>50</sub> = 5.0 ± 1.3 nM). Conjugation with N <sub>4</sub> (N <sub>4</sub> -L6-CPCR4) further improved hCXCR4 affinity to 0.6 ± 0.1 nM. [ <sup>99m</sup> Tc]Tc-N <sub>4</sub> -L6-CPCR4 also showed the most efficient internalization (97% of total cellular activity at 2 h) and the highest tumor accumulation (8.6 ± 1.3% iD/g, 1 h p.i.) of the compounds investigated. Therefore, [ <sup>99m</sup> Tc]Tc-N <sub>4</sub> -L6-CPCR4 (termed [ <sup>99m</sup> Tc]Tc-PentixaTec) was selected for first-in-human application. [ <sup>99m</sup> Tc]Tc-PentixaTec was well tolerated, exhibits a favorable biodistribution and dosimetry profile (2.1-3.4 mSv per 500 MBq) and excellent tumor/background ratios in SPECT and planar imaging.
The successive optimization of the amino acid composition of the linker structure and the N-terminal <sup>99m</sup> Tc-labeling strategies (mas <sub>3</sub> vs HYNIC vs N <sub>4</sub> ) has provided [ <sup>99m</sup> Tc]Tc-PentixaTec as a novel, highly promising CXCR4-targeted SPECT agent for clinical application. With its excellent CXCR4 affinity, efficient internalization, high uptake in CXCR4-expressing tissues, suitable clearance/biodistribution characteristics, and favorable human dosimetry, it holds great potential for further clinical use.
Keywords
Mice, Animals, Humans, Tissue Distribution, Mice, SCID, Tomography, Emission-Computed, Single-Photon/methods, Radionuclide Imaging, Neoplasms, CXCR4 imaging, Cancer, Pentapeptide tracer, Planar imaging, SPECT/CT, [99mTc]Tc-PentixaTec
Pubmed
Web of science
Open Access
Yes
Create date
13/09/2023 15:39
Last modification date
25/01/2024 7:27