Author: Knösel, Thomas ; Enke, Johanna S ; Kircher, Malte ; Enke, Johanna S. ; Märkl, Bruno ; Rinscheid, Andreas ; Reincke, Martin ; Brüdgam, Denise ; Bundschuh, Ralph A ; Pfob, Christian H. ; Reitsam, Nic G. ; Schottelius, Margret ; Lapa, Constantin ; Nittbaur, Bernd ; Ritzel, Kathrin ; Dierks, Alexander ; Wienand, Georgine ; Pfob, Christian H ; Asbach, Evelyn ; Reitsam, Nic G ; Bundschuh, Ralph A.

C-X-C motif chemokine receptor 4 (CXCR4)-directed imaging has gained clinical interest in aiding clinical diagnostics in primary aldosteronism (PA). We retrospectively evaluated the feasibility of CXCR4-directed scintigraphy using the novel CXCR-4 ligand [^99mTc]Tc-pentixatec in patients with PA. Methods: Six patients (mean age ± SD, 49 ± 15 y) underwent CXCR4-directed scintigraphy (including planar imaging and SPECT/CT) 30, 120, and 240 min after injection of 435 ± 50 MBq of [^99mTc]Tc-pentixatec. Adrenal CXCR4 expression was analyzed by calculating lesion-to-contralateral ratios (LCRs). Imaging results were correlated to clinical information. Histopathology and clinical follow-up served as the standard of reference. Results: Three subjects showed lateralization of adrenal tracer accumulation, with a mean maximum lesion-to-contralateral ratio of 1.65 (range, 1.52-1.70), which correlated with morphologic findings on CT. One individual underwent adrenalectomy and presented with complete biochemical and clinical remission at follow-up. Histopathologic workup confirmed unilateral aldosterone-producing adenoma. Conclusion: [^99mTc]Tc-pentixatec scintigraphy with SPECT in patients with PA is feasible and might offer a valuable alternative to CXCR4-directed imaging with [⁶⁸Ga]Ga-pentixafor PET.

01 Nov 2023·European journal of nuclear medicine and molecular imaging

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

Article

Author: Konrad, Matthias ; Janzen, Tilman ; Schottelius, Margret ; Pfob, Christian Helmut ; Wienand, Georgine ; Rinscheid, Andreas ; Nittbaur, Bernd ; Wester, Hans-Jürgen ; Lapa, Constantin

PURPOSEThe 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 ^99mTc-labeled cyclic pentapeptides based on the PentixaFor scaffold.METHODSSix mas₃-conjugated CPCR4 analogs with different 4-aminobenzoic acid (Abz)-D-Ala-D-Arg-aa₃ linkers (L1-L6) as well as the corresponding HYNIC- and N₄-analogs of L6-CPCR4 were synthesized via standard SPPS. Competitive binding studies (IC₅₀ and IC₅₀inv) were carried out using Jurkat T cell lymphoma cells and [¹²⁵I]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, [^99mTc]Tc-N₄-L6-CPCR4 ([^99mTc]Tc-PentixaTec) was selected for an early translation to the human setting. Five patients with hematologic malignancies underwent [^99mTc]Tc-N₄-L6-CPCR4 SPECT/planar imaging with individual dosimetry.RESULTSOf the six mas₃-conjugated peptides, mas₃-L6-CPCR4 (mas₃-dap-r-a-Abz-CPCR4) showed the highest CXCR4 affinity (IC₅₀ = 5.0 ± 1.3 nM). Conjugation with N₄ (N₄-L6-CPCR4) further improved hCXCR4 affinity to 0.6 ± 0.1 nM. [^99mTc]Tc-N₄-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, [^99mTc]Tc-N₄-L6-CPCR4 (termed [^99mTc]Tc-PentixaTec) was selected for first-in-human application. [^99mTc]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.CONCLUSIONThe successive optimization of the amino acid composition of the linker structure and the N-terminal ^99mTc-labeling strategies (mas₃ vs HYNIC vs N₄) has provided [^99mTc]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.

International Journal of Molecular Sciences

Comparative Preclinical Evaluation of Peptide-Based Chelators for the Labeling of DARPin G3 with 99mTc for Radionuclide Imaging of HER2 Expression in Cancer

Article

Author: Tolmachev, Vladimir ; Tretyakova, Maria ; Plotnikov, Evgenii ; Deyev, Sergey ; Konovalova, Elena ; Shabanova, Yulia ; Garousi, Javad ; Bezverkhniaia, Ekaterina ; Zelchan, Roman ; Vorobyeva, Anzhelika ; Larkina, Mariia ; Gräslund, Torbjörn ; Belousov, Mikhail ; Schulga, Alexey ; Yuldasheva, Feruza

Non-invasive radionuclide imaging of human epidermal growth factor receptor type 2 (HER2) expression in breast, gastroesophageal, and ovarian cancers may stratify patients for treatment using HER2-targeted therapeutics. Designed ankyrin repeat proteins (DARPins) are a promising type of targeting probe for radionuclide imaging. In clinical studies, the DARPin [99mTc]Tc-(HE)3-G3 labeled using a peptide-based chelator His-Glu-His-Glu-His-Glu ((HE)3), provided clear imaging of HER2 expressing breast cancer 2–4 h after injection. The goal of this study was to evaluate if the use of cysteine-containing peptide-based chelators Glu-Glu-Glu-Cys (E3C), Gly-Gly-Gly-Cys (G3C), and Gly-Gly-Gly-Ser-Cys connected via a (Gly-Gly-Gly-Ser)3-linker (designated as G3-(G3S)3C) would further improve the contrast of imaging using 99mTc-labeled derivatives of G3. The labeling of the new variants of G3 provided a radiochemical yield of over 95%. Labeled G3 variants bound specifically to human HER2-expressing cancer cell lines with affinities in the range of 1.9–5 nM. Biodistribution of [99mTc]Tc-G3-G3C, [99mTc]Tc-G3-(G3S)3C, and [99mTc]Tc-G3-E3C in mice was compared with the biodistribution of [99mTc]Tc-(HE)3-G3. It was found that the novel variants provide specific accumulation in HER2-expressing human xenografts and enable discrimination between tumors with high and low HER2 expression. However, [99mTc]Tc-(HE)3-G3 provided better contrast between tumors and the most frequent metastatic sites of HER2-expressing cancers and is therefore more suitable for clinical applications.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	DE	Technische Universität München	19 Aug 2023

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