Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin αvβ3 and the MC1 Receptor—Suitable for the Specific Visualization of Melanomas?
Abstract
:1. Introduction
2. Results and Discussion
2.1. General Considerations for the Design of the Heterobivalent SiFAlin-Modified Peptidic Ligands
2.2. Synthesis of the Heterobivalent SiFAlin-Modified Peptidic Ligands
2.3. 18F-Radiolabeling of 1–6 and Determination of Lipophilicity and Stability of [18F]1–[18F]6 in Human Serum
2.4. In Vitro Evaluation of 1–6 Regarding Their Binding Affinities to the Respective Target Receptors
2.5. Evaluation of the In Vivo Pharmacokinetics and Ex Vivo Biodistribution of [18F]2 and [18F]4
3. Materials and Methods
3.1. General
3.1.1. Chemistry
3.1.2. Radiolabeling
3.1.3. Competitive Binding Studies
3.1.4. In Vivo PET Imaging
3.1.5. Statistical Analyses
3.2. Chemical Syntheses
3.2.1. Synthesis of Peptides 7–9
3.2.2. Modification of the Peptides with Linker Structures to Obtain 10–21
3.2.3. Synthesis of SiFAlin-Carboxylic Acid 28 and SiFAlin-Modified Symmetrically Branching Framework 29
3.2.4. Conjugation of 10–21 to the SiFAlin-Modified Framework 29 to Obtain the Target HBPLs 1–6 via the Intermediates 30–35
3.3. 18F-Radiolabeling, Evaluation of logD(7.4), Stability and Binding Affinities for HBPLs 1–6
3.3.1. 18F-Radiolabeling of the HBPLs 1–6
3.3.2. LogD(7.4) Determination of [18F]1–[18F]6
3.3.3. Determination of the Stability of [18F]1–[18F]6 in Human Serum
3.3.4. Cell Culture
3.3.5. Competitive Displacement Studies on B16F10 and U87MG Cells
3.4. In Vivo PET/CT Imaging and Ex Vivo Biodistribution of [18F]2 and [18F]4
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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HBPL | Linker | RCP [%] | RCY [%] | Am [GBq/µmol] | A0 [GBq] | logD(7.4) | Stability * [%] |
---|---|---|---|---|---|---|---|
[18F]1 | PEG1 | ≥98 | 27.2 ± 1.4 | 17.5–28.6 | 1.0–1.6 | −1.08 ± 0.07 | 87.0 ± 2.3 |
[18F]2 | PEG3 | ≥98 | 40.3 ± 2.6 | 20.0–31.2 | 0.8–1.2 | −1.19 ± 0.05 | 85.4 ± 2.8 |
[18F]3 | PEG5 | ≥97 | 50.4 ± 3.1 | 25.1–49.8 | 0.9–2.0 | −1.15 ± 0.01 | 81.4 ± 2.9 |
[18F]4 | PEG8 | ≥97 | 38.4 ± 0.6 | 25.7–42.7 | 1.1–1.9 | −1.39 ± 0.03 | 83.6 ± 0.8 |
[18F]5 | DIG | ≥95 | 27.3 ± 9.9 | 17.0–47.6 | 1.8–2.2 | −1.21 ± 0.01 | 83.2 ± 2.4 |
[18F]6 | Ox-EGEGE | ≥97 | 43.2 ± 1.6 | 39.3–51.4 | 1.2–1.9 | −1.52 ± 0.01 | 82.7 ± 1.8 |
Compound | IC50 (B16F10) [nM] | Compound | IC50 (U87MG) [nM] |
---|---|---|---|
1 | 1.74 ± 0.25 | 1 | 2881 ± 757 |
2 | 0.99 ± 0.11 | 2 | 1300 ± 288 |
3 | 3.44 ± 0.09 | 3 | 1911 ± 70 |
4 | 6.00 ± 0.47 | 4 | 2034 ± 323 |
5 | 2.05 ± 0.35 | 5 | 5895 ± 722 |
6 | 4.18 ± 0.32 | 6 | >100,000 |
α-MSH | 3.75 ± 0.61 | c(RGDfC) | 1493 ± 210 |
NDP | 0.17 ± 0.04 | c(RGDfK) | 427 ± 37 |
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Cheng, X.; Hübner, R.; von Kiedrowski, V.; Fricker, G.; Schirrmacher, R.; Wängler, C.; Wängler, B. Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin αvβ3 and the MC1 Receptor—Suitable for the Specific Visualization of Melanomas? Pharmaceuticals 2021, 14, 547. https://doi.org/10.3390/ph14060547
Cheng X, Hübner R, von Kiedrowski V, Fricker G, Schirrmacher R, Wängler C, Wängler B. Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin αvβ3 and the MC1 Receptor—Suitable for the Specific Visualization of Melanomas? Pharmaceuticals. 2021; 14(6):547. https://doi.org/10.3390/ph14060547
Chicago/Turabian StyleCheng, Xia, Ralph Hübner, Valeska von Kiedrowski, Gert Fricker, Ralf Schirrmacher, Carmen Wängler, and Björn Wängler. 2021. "Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin αvβ3 and the MC1 Receptor—Suitable for the Specific Visualization of Melanomas?" Pharmaceuticals 14, no. 6: 547. https://doi.org/10.3390/ph14060547