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

2023; Springer Science+Business Media; Volume: 50; Issue: 13 Linguagem: Inglês

10.1007/s00259-023-06395-x

1619-7089

Matthias Konrad, Andreas Rinscheid, Georgine Wienand, Bernd Nittbaur, Hans‐Jürgen Wester, Tilman Janzen, Constantin Lapa, Christian H. Pfob, Margret Schottelius,

Monoclonal and Polyclonal Antibodies Research

Abstract Purpose The clinical success non-invasive imaging of CXCR4 expression using [ 68 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 99m Tc-labeled cyclic pentapeptides based on the PentixaFor scaffold. Methods Six mas 3 -conjugated CPCR4 analogs with different 4-aminobenzoic acid (Abz)-D-Ala-D-Arg-aa 3 linkers ( L1–L6 ) as well as the corresponding HYNIC- and N 4 -analogs of L6- CPCR4 were synthesized via standard SPPS. Competitive binding studies (IC 50 and IC 50 inv) were carried out using Jurkat T cell lymphoma cells and [ 125 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, [ 99m Tc]Tc-N 4 - L6- CPCR4 ([ 99m Tc]Tc-PentixaTec) was selected for an early translation to the human setting. Five patients with hematologic malignancies underwent [ 99m Tc]Tc-N 4 - L6 -CPCR4 SPECT/planar imaging with individual dosimetry. Results Of the six mas 3 -conjugated peptides, mas 3 -L6 -CPCR4 (mas 3 -dap-r-a-Abz-CPCR4) showed the highest CXCR4 affinity (IC 50 = 5.0 ± 1.3 nM). Conjugation with N 4 (N 4 - L6 -CPCR4) further improved hCXCR4 affinity to 0.6 ± 0.1 nM. [ 99m Tc]Tc-N 4 - 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, [ 99m Tc]Tc-N 4 - L6 -CPCR4 (termed [ 99m Tc]Tc-PentixaTec) was selected for first-in-human application. [ 99m 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. Conclusion The successive optimization of the amino acid composition of the linker structure and the N-terminal 99m Tc-labeling strategies (mas 3 vs HYNIC vs N 4 ) has provided [ 99m 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. Graphical abstract