[99mTc]Tc-PentixaTec: development, extensive pre-clinical evaluation, and first human experience.

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License: CC BY 4.0
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
Author(s)
Konrad M., Rinscheid A., Wienand G., Nittbaur B., Wester H.J., Janzen T., Lapa C., Pfob C.H., Schottelius M.
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
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.
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
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