Radiotracers for Positron Emission Tomography
Development of Novel Methods for the Synthesis of Enantiomerically Pure Fluorinated Amino Acids Labeled with Fluorine-18, Radiotracers for Positron Emission Tomography (PET)
Tech Area / Field
- CHE-SYN/Basic and Synthetic Chemistry/Chemistry
- MED-DID/Diagnostics & Devices/Medicine
8 Project completed
Senior Project Manager
Bunyatov K S
INEOS (Organo-Element Compounds), Russia, Moscow
- Institute of Human Brain, Russia, St Petersburg\nYerevan State University, Armenia, Yerevan
- University of London / King's College London / Department of Chemistry, UK, London\nABX Advanced Biochemical Compounds, Germany, Radeberg\nArgos Zyklotron, Austria, Linz\nKarolinska Institute, Sweden, Stockholm\nUniversite de Paris-Sud / Institut de Chimie Moleculaire et des Materiaux D’Orsay, France, Orsay
Project summaryThe project objective is the development of new synthetic methods for fluorinated -amino acids labeled with short-lived fluorine-18 for their use as radiotracers in Positron Emission Tomography (PET). PET technique is rapidly becoming a major diagnostic imaging tool. The most common application of PET belongs to determining the presence, severity and staging of cancers, its recurrences and response to treatment. In addition, PET has significant applications in diagnosing Alzheimer’s and Parkinson’s disease, epilepsy and others. It is a modern tool for evaluation of myocardial perfusion and viability, important criteria for patient’s selection for a revascularisation.
To date more than 700 PET sites are functioning within the United States alone with more than 200,000 scans per year.
PET involves the administration of a tracer molecule (PET radiotracer) that is radio-labeled with short-lived positron emitting isotopes (e.g. 11C, T1/2=20.4 min or 18F, T1/2=110 min). Special synthetic methods are required for the preparation of PET tracers because of the short half-lives and submicromole quantities involved. More than 80% of clinical PET studies are based on the 2-18F-fluoro-deoxy-D-glucose ([18F]FDG), fluorinated analogue of glucose. A major limitation of the [18F]FDG belongs to a high physiological background in brain which results in low contrast images of the tumors and difficulties in distinguishing between gray matter and benign tumors. The implementation of new classes of RPs with different uptake mechanisms as compared to 18F-FDG is urgently needed.
Use of labeled amino acids (AA) provides a higher contrast delineation of brain tumors as compared with [18F]FDG. However, a number of AA used routinely for PET oncology diagnostics is limited by L-[11C-methyl]methionine (MET) mainly due to the easy of its synthesis. The short half-life of 11C (20.4 min) restricts its utilization to a few PET centers equipped with expensive in-house cyclotrons and radiochemistry. For this reason in the past few years the interest of PET community has been focused to a great extent on fluorinated AA (FAA) labeled with long living 18F (T1/2=110 min) isotope, as the FAA could be particularly useful for PET-units remote from any cyclotrons. Despite these compounds being found extremely useful as PET imaging agents, their implementation into routine practice has been restricted mainly by rather inefficient radioactive synthesis. The major synthetic problem has been the introduction of the 18F-label into a selected position of the given AA in its L- (or S)-configuration. As only this enantiomer of amino acids is active in metabolism and the presence of another D- (or R)-enantiomer is decreasing the visual effectiveness of the procedure, the enantiomeric purity of the AA is of paramount importance.
Two of the applying groups (Moscow and Erevan) are completing their previous project A-356 as supported by ISTC entitled “New Chiral Auxiliaries and Catalysts for the Asymmetric Synthesis of None-proteinogenic Amino Acids.” As a result of the scientific efforts within that project, novel efficient stoichiometric and catalytic phase transfer methods of asymmetric synthesis of unlabeled a-amino acids were developed based on use of chiral or achiral Ni(II) complexes of Schiff’s bases of glycine and (S)-[N-(N-benzyl)prolylamino]benzophenone (BPB) or 2-(N-pyridine-2-carbonyl)amunobenzophenone (PBP) correspondingly.
At the same time a co-operation between the two teams-applicants from Moscow and St. Petersburg was established with an intention to implement some of these developments into the preparation of 11C- and 18F-labeled AA for PET application. Two important [18F]FAA, namely 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine (6-FDOPA), well established RPs for PET evaluation of the integrity of dopaminergic system and recently applied for evaluation of tumors, and 2-[18F]fluoro-L-tyrosine (2-FTYR), a promising candidate for PET oncology, have been labeled using both the stoichiometric and the phase transfer chiral catalytic approaches. In contrast to previously developed and published methods for amino acid synthesis, the chiral alkylation was performed under very mild conditions, using stable reagents (chiral and achiral Ni(II) complexes and/or chiral catalysts) and the key synthetic step took several minutes for completion. This approach looked very attractive for the automated production of PET RPs. A patent application was filed recently on behalf of Moscow - St-Petersburg team with the participation of ABX company, Germany (S.M. Ametamey, R.N. Krasikova, O.S. Fedorova, Yu. N. Belokon, S. Vyskocyl. “Verfahren zur Herstellung von 18F-fluorierten alpha – Aminosaren”. Deutsche Patentanmeldung Nr. 102 23 451.5. Submitted on May, 25, 2002 via industrial partner, ABX advanced biochemical compounds, Germany).
Evidently, novel vistas were opened in the field of PET RPs and additional efforts are urgently needed for its broad practical implementation and further scientific development.
We put ourselves the following exploratory tasks:
1. Further improvements in the design of chiral auxiliaries and the synthesis of a new generation of BPB based reagents via the introduction of electron-withdrawing substituents into the phenyl ring attached to the carbonyl group.
2. Development of new methods of fluorine introduction into the phenyl moiety of enantiomerically enriched amino acids without their racemization, employing Ni(II) complexes as protective groups for both amino and carboxyl groups. Such methods may include Pd mediated substitution of [18F]-fluorine for halogen substituent and/or use of Cr(CO)3 activation of the phenyl ring for the nucleophilic substitution of an active leaving group with an activated [18F]-fluoride complex.
Applied section of the project embrace:
1. The evaluation of a stoichiometric asymmetric method for its potential to be applied in a routine production with PET. Within this task we will investigate the chiral alkylation step in the synthesis of [18F]FAA under a wide range of reaction conditions (time, temperature, solvent, nature of the base, amounts of the reagents) with different chiral Ni(II) complexes derived from Ni(BPB)Gly – to find the optimal conditions providing high radiochemical yield and enantiomeric purity of [18F]FAA in a reproducible manner.
2. Phase transfer catalytic (PTC) alkylation of achiral Ni(II) complex will be further elaborated for labeled amino acid production.
3. The final stage of the project will be devoted to the detailed tuning of the methods developed in the first section for the stereoselective radiolabeling of FAA with 18F. The optimal method (based on either stoichiometric or PTC chiral alkylation) will be chosen as a rationale base for routine production of [18F]FAA.
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