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Novel routes to 18F-labelled amino acids and vitamin derivatives useful for non-invasive, nuclear imaging of oncological and neurodegenerative diseases

English title Novel routes to 18F-labelled amino acids and vitamin derivatives useful for non-invasive, nuclear imaging of oncological and neurodegenerative diseases
Applicant Schibli Roger
Number 152360
Funding scheme SCOPES
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Organic Chemistry
Start/End 01.05.2014 - 30.04.2016
Approved amount 178'080.00
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All Disciplines (2)

Discipline
Organic Chemistry
Pharmacology, Pharmacy

Keywords (6)

Radiotracer; Positron Emission Tomography; Amino acid; Vitamin B6; Nucleophilic Substitution ; F-DOPA

Lay Summary (German)

Lead
Die Positronen Emission Tomographie (PET) ist heute eine etablierte Methode in der medizinischen Bildgebung zur Erkennung von Krebs, neurodegenerative und kardiovaskuläre Erkrankungen. Weltweit wird deshalb massiv in neue PET-Zentren investiert. Derzeit ist die 2-[18F]Fluor-2-deoxy-D-glucose ([18F]FDG) für mehr als 80 % aller klinischen PET-Scans verantwortlich obwohl in vielen Indikationen ihre Spezifität ungenügend ist. Deshalb nimmt die Nachfrage nach neuen, spezifischeren PET-Tracern ständig zu. Die kurze physkalische Halbwertszeit von 18F (110 min) wiederum verlangt nach einem raschen und effizienten, chemischen Einbau des Radionuklids in neue und bekannte Biomoleküle u.a. Aminosäuren.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Der Aminosäure Radiotracer 6-[18F]-Fluor-L-DOPA (dihydroxyphenylalanine) ist von großem Interesse in der Psychiatrie und Onkologie. Die gängige Radiosynthese basiert auf einer ineffizienten Methode (elektrophile Substitution)  ausgehend von  18F[F2]-Gas, was zu einer tiefen spezifischen Radioaktivität führt.

Ein Teilziel dieses Projekts ist deshalb die Entwicklung einer alternativen Syntheseroute für  6-[18F]-Fluor-L-DOPA  (via automatisierter, nukleophiler Substitution). Die Methode solle sich auch auf andere aromatische Aminosäuren und deren Derivate übertragen lassen. Wir wollen L–DOPA an der C-alpha-Position nukleophil, radioaktiv substituieren. Zu diesem Zweck werden wir neuartige Ni(II)- Aminosäure-Komplex als Vorstufe zur Radiomarkierung herstellen und einsetzen. Neben der L-Form, werden wir auch die D-Form der Aminosäuren herstellen und in vitro bzw. in vivo testen.

Das zweite Ziel des Projekts ist die Radiosynthese eines Pyridoxal-basierten Tracers für onkologische und neurologische Anwendungen in der Nuklearmedizin. Pyridoxal -5'-Phosphat-abhängige (Vitamin B6 ) Enzyme spielen eine zentrale Rolle im Metabolismus von Aminosäuren und damit für das Zellwachstum. Wir werden wiederum durch nukleophile Substitution neuartige 18F-markierte Analoga von Pyridoxin herstellen und in vitro und in vivo im Mausmodell studieren.

Wissenschaftlicher und gesellschaftlicher Kontext des Projekts

Radiotracer, wie sie in diesem Projekt entwickelt werden sollen, sind ein wichtiges Werkzeug für die personalisierte Medizin der Zukunft. Die Zusammenarbeit und das Know-how zwischen den Partnern innerhalb des Projekts sind hoch synergistisch. Die bisherige Arbeiten des armenischen Partners auf dem Gebiet der selektiven, chiralen Synthese von Aminosäuren und das Know-how des Russischen und Schweizer Partner auf dem Gebiet der Radiosynthese mit 18F sind ideale Voraussetzungen für den Erfolg des Projekts.

Direct link to Lay Summary Last update: 09.04.2014

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Deprotection step optimization in asymmetric nucleophilic synthesis of 6-[18F]-L-FDOPA
Fedorova, Olga, Orlovskaja Victoria, Kuznetsova Olga, Belokon Yu, Maleev Victor, Mu Linjing, Schibli Roger, Ametamey Simon, Saghyan Ashot, Krasikova Raisa (2015), Deprotection step optimization in asymmetric nucleophilic synthesis of 6-[18F]-L-FDOPA, SRC Burnasyan Federal Medical Biophysical Center of FMBA, Moscow.
The approach to direct nucleophilic synthesis of 18F-fluorinated aromatic amino acids labeled in alpha fluoromethyl group
Kuznetsova Olga, Orlovskaja Victoria, Fedorova Olga, Maleev Victor, Belokon Yu, Geolchanyan Arpine, Saghyan Ashot, Mu Linjing, Schibli Roger, Ametamey Simon, Krasikova Raisa (2015), The approach to direct nucleophilic synthesis of 18F-fluorinated aromatic amino acids labeled in alpha fluoromethyl group, SRC Burnasyan Federal Medical Biophysical Center of FMBA, Moscow.
The phase-transfer catalytic asymmetric nucleophilic synthesis of 6-[18F]fluoro-L-DOPA with simplified hydrolysis/cleavage of the protective groups
Orlovskaja Victoria Fedorova Olga Kuznetsova Olga Maleev Vladmir Belokon Andrey Geolchany (2015), The phase-transfer catalytic asymmetric nucleophilic synthesis of 6-[18F]fluoro-L-DOPA with simplified hydrolysis/cleavage of the protective groups, Elsevier B.V., Amsterdam.
Metallocomplex precursors for the synthesis of 18F-fluorinated aromatic amino acids labeled in alpha fluoromethyl moiety
Geolchanyan Arpine, Saghyan Ashot, Mkrtchyan Anna, Petrosyan Satenik, Simonyan Hayarpi, Maleev Olga, Belokon Daria, Schibli Roger, Krasikova Raisa, Metallocomplex precursors for the synthesis of 18F-fluorinated aromatic amino acids labeled in alpha fluoromethyl moiety, Springer, Cham.

Collaboration

Group / person Country
Types of collaboration
Simon Ametamey/ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Russian Academy of Sciences Russia (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Yerevan State University Armenia (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved


Associated projects

Number Title Start Funding scheme
157763 MobiPET: A mobile, small animal PET scanner for molecular imaging 01.03.2015 R'EQUIP

Abstract

Nowadays, Positron Emission Tomography (PET) is an established and pre- and clinically relevant methodology for non-invasive, molecular imaging. At present, there is an unprecedented investment in PET technology platforms including cyclotrons and hybrid imaging scanners (PET/CT and PET/MRI) all over the world. This stimulates the intense search for new radioactive molecular probes for oncological and neuronal indications. At present 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), is responsible for more than 80% of all clinical PET scans. 18F-labeled compounds are considered as the most suitable candidates for clinical PET due to favorable chemical and physical properties of the radionuclide 18F, leading to high spatial resolution in PET and a suitable physical half-life (110 min) allowing centralized production and quality control and economic distribution to remote PET centers. Efficient high yield radiolabeling reactions are essential for a widespread application of an 18F-radiotracer. Apart from [18F]FDG, amino acid based radiotracers such as 6-[18F]fluoro-L-DOPA are of significant interest in nuclear medicine. However, 6-[18F]fluoro-L-DOPA is produced by electrophilic substitution using 18F[F2] which leads to inherently low radiolabeling yields. Despite great efforts currently made by many groups to find a simple and easy-to-automate nucleophilic route for the introduction of 18F-isotope into aromatic ring systems, attempts have largely failed till today. Thus, one goal of the present JRP is the development of novel nucleophilic synthetic routes for the preparation of new 18F-labeled amino acids for use in oncology and neurology. The strategy will be demonstrated using a novel [18F]fluoro-L-DOPA derivative, including in vitro and in vivo assessment. Sub-project 1: We will prepare a novel 18F-labelled derivative of L-DOPA that is not radiolabeled at the aromatic ring structure but via the C-alpha position via direct nucleophilic substitution. Based on previous experience of the project participants in asymmetric synthesis of 18F-fluorinated amino acids we suggest a simple labeling route for [18F]fluoromethyl-a-3,4-dihydroxy-L-phenyl alanine ([18F]FMe-L-DOPA) with the use of a novel enantiomerically pure Ni(II) amino acid complex as radiolabeling precursor. Besides being a new efficient, radiosynthetic route there is reason to speculate that by virtue of the presence of a fluoromethyl group, the [18F]FMe-L-DOPA features an alternative, metabolic route than 6-[18F]FDOPA. In addition [18F]FMe-D-DOPA could be prepared using the same strategy while changing the precursor structure from S- to R-form for evaluation of its potential in peripheral tumors imaging. Since recently the D-forms of amino acids are considered as promising tumor seeking agents for certain types of malignancies, however, it is not yet used in humans. Sub-project 2: A second goal of the JRP is the radiosynthesis of a pyridoxal-based tracer for potential oncological and neurological application. Pyridoxal-5'-phosphate (vitamin B6)-dependent enzymes play central roles in the metabolism of amino acids. Moreover, the synthesis of polyamines, which are essential for cell growth, and of biogenic amines, such as histamine and other signal transmitters, relies on these enzymes. The only [18F]fluoropyridoxal derivative reported was prepared via electrophilic route. We will synthesize via nucleophilic substitution two novel 18F-labelled analogs of pyridoxine and evaluate them in preclinical studies Because of the characteristics mentioned above, the pro-drug pyridoxine could be useful for tracking and visualizing the pyridoxal metabolism in normal and pathological conditions. The co-operation between the partners and their expertise is highly synergistic. The previous work of an Armenian partner on the development of highly selective chiral auxiliaries resulted in the preparation of a wide series of amino acids, thus ensuring successful performance of the organic synthesis (labeling precursors and references). Radiosynthesis of several 18F-labelled amino acids and other 18F-radiotracers has been elaborated by both Russian and Swiss applicants.
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