Shuttle–Cargo Fusion Molecules of Transport Peptides and the hD<sub>2/3</sub>Receptor Antagonist Fallypride: A Feasible Approach To Preserve Ligand–Receptor Binding?

Wängler, Carmen; Chowdhury, Subrata; Höfner, Georg; Djurova, Petia; Purisima, Enrico O.; Bartenstein, Peter; Wängler, Björn; Fricker, Gert; Wanner, Klaus T.; Schirrmacher, Ralf

doi:10.1021/jm5004123

Cited by 7 publications

(11 citation statements)

References 63 publications

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Section: Radiolabeled Peptides For Diagnostic Imagingmentioning

confidence: 98%

“…Chemical structure of 18 F-SiFA-containing TfR targeting peptide HAIYPRH (TfR-P s ) TfR-P s -SiFA-PEG 3 ( 18 F- 28 ) …”

Section: Radiolabeled Peptides For Diagnostic Imagingmentioning

confidence: 99%

“…A report presenting a potential strategy to deliver neuroreceptor ligands across the highly restrictive blood-brain barrier (BBB) has also recently illustrated an additional application of the 18 F-SiFA technique. 67 Although limited to in vitro results, this study suggests a conceptual framework in which small molecule ligands which bind receptors within the central nervous system (CNS) are bound to endogenous peptide transported through transcytosis. One of the peptide−small molecule constructs delineated in this study was a transferrin receptor binding peptide (TfR) fused with the dopamine D 2 receptor antagonist fallypride and bearing a linker decorated with a 18 F-SiFA prosthetic ( 18 F-28, Figure 7).…”

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confidence: 99%

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From Unorthodox to Established: The Current Status of ¹⁸F-Trifluoroborate- and ¹⁸F-SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging

et al. 2015

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Unorthodox (18)F-labeling strategies not employing the formation of a carbon-(18)F bond are seldom found in radiochemistry. Historically, the formation of a boron- or silicon-(18)F bond has been introduced very early on into the repertoire of labeling chemistries, but is without translation into any clinical radiotracer besides inorganic B[(18)F]F4(-) for brain tumor diagnosis. For many decades these labeling methodologies were forgotten and have just recently been revived by a handful of researchers thinking outside the box. When breaking with established paradigms such as the inability to obtain labeled compounds of high specific activity via isotopic exchange or performing radiofluorination in aqueous media, the research community often reacts skeptically. In 2005 and 2006, two novel labeling methodologies were introduced into radiochemistry for positron emission tomography (PET) tracer development: RBF3(-) labeling reported by Perrin et al. and the SiFA methodology by Schirrmacher, Jurkschat, and Waengler et al. which is based on isotopic exchange (IE). Both labeling methodologies have been complemented by other noncanonical strategies to introduce (18)F into biomolecules of diagnostic importance, thus profoundly enriching the landscape of (18)F radiolabeling. B- and Si-based labeling strategies finally revealed that IE is a viable alternative to established and traditional radiochemistry with the advantage of simplifying both the labeling effort as well as the necessary purification of the radiotracer. Hence IE will be the focus of this contribution over other noncanonical labeling methods. Peptides for tumor imaging especially lend themselves favorably toward one-step labeling via IE, but small molecules have been described as well, taking advantage of these new approaches, and have been used successfully for brain imaging. This Review gives an account of both radiochemistries centered on boron and silicon, describing the very beginnings of their basic research, the path that led to optimization of their chemistries, and the first encouraging preclinical results paving the way to their clinical use. This side by side approach will give the reader the opportunity to follow the development of a new basic discovery into a clinically applicable radiotracer including all the hurdles that have had to be overcome.

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Section: Radiolabeled Peptides For Diagnostic Imagingmentioning

confidence: 98%

“…Chemical structure of 18 F-SiFA-containing TfR targeting peptide HAIYPRH (TfR-P s ) TfR-P s -SiFA-PEG 3 ( 18 F- 28 ) …”

Section: Radiolabeled Peptides For Diagnostic Imagingmentioning

confidence: 99%

mentioning

confidence: 99%

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From Unorthodox to Established: The Current Status of ¹⁸F-Trifluoroborate- and ¹⁸F-SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging

et al. 2015

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“…3b). Thus, the proline residue in r D-HAI seems to be a key pharmacophoric site 35,40 that leads to an improvement in transport when substituted by a bulkier residue.…”

Section: Resultsmentioning

confidence: 99%

A MALDI-TOF-based Method for Studying the Transport of BBB Shuttles—Enhancing Sensitivity and Versatility of Cell-Based In Vitro Transport Models

Arranz‐Gibert

Guixer

Prades

et al. 2019

Sci Rep

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In recent decades, peptide blood-brain barrier shuttles have emerged as a promising solution for brain drugs that are not able to enter this organ. The research and development of these compounds involve the use of in vitro cell-based models of the BBB. Nevertheless, peptide transport quantification implies the use of large amounts of peptide (upper micromolar range for RP-HPLC-PDA) or of derivatives (e.g. fluorophore or quantum-dot attachment, radiolabeling) in the donor compartment in order to enhance the detection of these molecules in the acceptor well, although their structure is highly modified. Therefore, these methodologies either hamper the use of low peptide concentrations, thus hindering mechanistic studies, or do not allow the use of the unmodified peptide. Here we successfully applied a MALDI-TOF MS methodology for transport quantification in an in vitro BBB cell-based model. A light version of the acetylated peptide was evaluated, and the transport was subsequently quantified using a heavy internal standard (isotopically acetylated). We propose that this MALDI-TOF MS approach could also be applied to study the transport across other biological barriers using the appropriate in vitro transport models (e.g. Caco-2, PAMPA).

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“…[179] Als niedermolekulare Verbindung wurde Fallyprid gewählt, ein Bindungspartner von Neurorezeptoren (hD2/3), der im Menschen mithilfe von Positronenemissionstomographie (PET) gut beschrieben wurde,u nd die Peptide wurden nach ihrer Fähigkeit ausgesucht, über rezeptorvermittelte Tr anszytose (TfR-bindende Peptide oder AngioPep-2) oder adsorptive Tr anszytose (TAT,T AT49-57, Tr ansportan, Penetratin und die nukleare Lokalisationssequenz des humanen NF-kB) ins Gehirn zu gelangen. Da der Tr ansport von Peptiden zum Gehirn schwierig sein kann, wurden in einer frühen konzeptionellen Studie niedermolekulare Verbindungen als Tr äger oder "trojanische Pferde" für die Überwindung der Blut-Hirn-Schranke vorgeschlagen, und die Durchführbarkeit in vitro wurde demonstriert.…”

Section: Aufsätzeunclassified

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

et al. 2017

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Unsere sich stetig erweiternden Kenntnisse über biologische Systeme haben eine Vielzahl an hoch interessanten neuen biologischen Zielstrukturen aufgedeckt, deren Modulation möglicherweise neuartige Therapiemöglichkeiten für viele Krankheiten erschließt. Diese Angriffspunkte umfassen insbesondere Protein‐Protein‐ und Protein‐Nukleinsäure‐Wechselwirkungen, die jedoch durch klassische niedermolekulare Substanzen oftmals nicht adressierbar sind. Andere Substanzklassen oder Modalitäten werden daher benötigt, um diese Ziele anzuvisieren. Einige akademische Forschungsgruppen und pharmazeutische Unternehmen greifen daher zunehmend das Konzept der so genannten “neuen Modalitäten” auf. Dieser Aufsatz definiert erstmals diesen Begriff, der neuartige Peptidgerüststrukturen, Oligonukleotide, Hybride, molekulare Konjugate sowie auf neuartige Weise eingesetzte, klassische niedermolekulare Verbindungen berücksichtigt. Wir stellen die repräsentativsten Beispiele dieser Modalitäten vor, die auf große Bindungsoberflächen, wie sie in Protein‐Protein‐Wechselwirkungen vorkommen, sowie auf zentrale biologische Zellregulationsvorgänge abzielen.

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Shuttle–Cargo Fusion Molecules of Transport Peptides and the hD_2/3Receptor Antagonist Fallypride: A Feasible Approach To Preserve Ligand–Receptor Binding?

Cited by 7 publications

References 63 publications

From Unorthodox to Established: The Current Status of ¹⁸F-Trifluoroborate- and ¹⁸F-SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging

From Unorthodox to Established: The Current Status of ¹⁸F-Trifluoroborate- and ¹⁸F-SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging

A MALDI-TOF-based Method for Studying the Transport of BBB Shuttles—Enhancing Sensitivity and Versatility of Cell-Based In Vitro Transport Models

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

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Shuttle–Cargo Fusion Molecules of Transport Peptides and the hD2/3Receptor Antagonist Fallypride: A Feasible Approach To Preserve Ligand–Receptor Binding?

Cited by 7 publications

References 63 publications

From Unorthodox to Established: The Current Status of 18F-Trifluoroborate- and 18F-SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging

From Unorthodox to Established: The Current Status of 18F-Trifluoroborate- and 18F-SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging

A MALDI-TOF-based Method for Studying the Transport of BBB Shuttles—Enhancing Sensitivity and Versatility of Cell-Based In Vitro Transport Models

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

Contact Info

Product

Resources

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Shuttle–Cargo Fusion Molecules of Transport Peptides and the hD_2/3Receptor Antagonist Fallypride: A Feasible Approach To Preserve Ligand–Receptor Binding?

From Unorthodox to Established: The Current Status of ¹⁸F-Trifluoroborate- and ¹⁸F-SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging

From Unorthodox to Established: The Current Status of ¹⁸F-Trifluoroborate- and ¹⁸F-SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging