Fluorine and Health

Molecular Imaging, Biomedical Materials and Pharmaceuticals

Alain Tressaud, Gunter Haufe

• Publisher: Elsevier Science
• Year: 2008
• ISBN:
  9780080558110
• Topic: Medicine
• Subtopic: Public Health, Administration & Care

Fluorine and Health presents a critical multidisciplinary overview on the contribution of fluorinated compounds to resolve the important global issue of medicinal monitoring and health care. The involved subjects are organized in three thematic parts devoted to Molecular Imaging, Biomedical Materials and Pharmaceuticals. Initially the key-position of partially fluorinated low molecular weight compounds labelled either with the natural 19F-isotope for Magnetic Resonance Imaging (MRI) or labelled with the radioactive [18F]-isotope for Positron Emission Tomography (PET) is highlighted. Both non-invasive methods belong to the most challenging in vivo imaging techniques in oncology, neurology and in cardiology for the diagnosis of diseases having the highest mortality in the industrialized countries. The manifold facets of fluorinated biomaterials range from inorganic ceramics to perfluorinated organic molecules. Liquid perfluorocarbons are suitable for oxygen transport and as potential respiratory gas carriers, while fluorinated polymers are connected to the pathology of blood vessels. Another important issue concerns the application of highly fluorinated liquids in ophthalmology. Moreover, fluorine is an essential trace element in bone mineral, dentine and tooth enamel and is applied for the prophylaxis and treatment of dental caries. The various origins of human exposure to fluoride species is detailed to promote a better understanding of the effect of fluoride species on living organisms.Medicinally relevant fluorinated molecules and their interactions with native proteins are the main focus of the third part. New molecules fluorinated in strategic position are crucial for the development of pharmaceuticals with desired action and optimal pharmacological profile. Among the hundreds of marketed active drug components there are more than 150 fluorinated compounds. The chapters will illustrate how the presence of fluorine atoms alters properties of bioactive compounds at various biochemical steps, and possibly facilitate its emergence as pharmaceuticals. Finally the synthetic potential of a fluorinase, the first C-F bond forming enzyme, is summarized.

• New approach of topics involving chemistry, biology and medicinal techniques
• Transdisciplinar papers on fluoride products
• Importance of fluoride products in health
• Updated data on specific topics

Part I

Molecular Imaging

Chapter 1 Fluorine‐18 Chemistry for Molecular Imaging with Positron Emission Tomography

Chapter 2 Application of 18F‐PET Imaging for the Study of Alzheimer’s Disease

Chapter 3 18F‐Labeled PET‐Tracers for Cardiological Imaging

Chapter 4 [18F]‐Labeled PET and PET/CT Compounds in Oncology

Chapter 5 Non‐Invasive Physiology and Pharmacology Using 19F Magnetic Resonance

Chapter 1

Fluorine‐18 Chemistry for Molecular Imaging with Positron Emission Tomography

Frédéric Dollé^1,*, Dirk Roeda¹, Bertrand Kuhnast¹ and Marie‐Claire Lasne², ¹Institut d’Imagerie Biomédicale, CEA, Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, F‐91401 Orsay cedex, France, ²CNRS, Département Chimie, 3 Rue Michel Ange, 75794 Paris cedex, France, *Corresponding author. Tel.: +33‐(0)1‐69‐86‐77‐04; Fax: +33‐(0)1‐69‐86‐77‐49, E-mail: [email protected]

Abstract

Molecular in vivo imaging with the high‐resolution and sensitive positron emission tomography (PET) technique requires the preparation of positron‐emitting radiolabelled probes or radiotracers. For this purpose, fluorine‐18 is becoming increasingly the radionuclide of choice due to its adequate physical and nuclear characteristics. The successful use in clinical oncology of 2‐[¹⁸F]fluoro‐2‐deoxy‐d‐glucose ([¹⁸F]FDG), currently the most widely used PET radiopharmaceutical, is manifestly also the motor behind the growing availability and interest for this positron emitter in radiopharmaceutical chemistry. The use of fluorine‐18, however, presents some drawbacks, in particular the limited options in labelling strategies. Besides a few exceptions, radiofluorinations can be classified into two categories: nucleophilic and electrophilic reactions. The nucleophilic reactions usually involve no‐carrier‐added (high‐specific‐radioactivity) [¹⁸F]fluoride as its K[¹⁸F]F‐K₂₂₂complex and include S_N2‐type substitutions in the aliphatic series and S_NAr‐type substitutions in the homoaromatic and heteroaromatic (particularly the pyridine family) series. The electrophilic reactions mainly use molecular [¹⁸F]fluorine of moderately low specific radioactivity, or reagents prepared from it such as acetyl [¹⁸F]hypofluorite, and include additions across double bonds, reactions with carbanions and especially fluorodehydrogenation and fluorodemetallation, where tin clearly appears to be the metal of choice. This chapter presents the bases and some recent advances in the field of fluorine‐18 radiochemistry and highlights the potential of this radioisotope in the design and preparation of fluorine‐18‐labelled probes for PET imaging, often drug based but also macromolecules of biological interest such as peptides, proteins and oligonucleotides.

1 INTRODUCTION

Positron emission tomography (PET) is a high‐resolution, sensitive, functional‐imaging technique in nuclear medicine that permits repeated, non‐invasive assessment and quantification of specific biological and pharmacological processes at the molecular level in humans and animals. It is the most advanced technology currently available for studying in vivo molecular interactions in terms of distribution, pharmacokinetics and pharmacodynamics [1]. Molecular PET imaging requires the preparation of a positron‐emitting radiolabelled probe or radiotracer [2,3]. For this purpose, fluorine‐18 is becoming increasingly the radionuclide of choice not only due to its adequate physical and nuclear characteristics but also due to the successful use in clinical oncology of 2‐[¹⁸F]fluoro‐2‐deoxy‐d‐glucose ([¹⁸F]FDG), currently the most widely used PET radiopharmaceutical and manifestly a motor behind the growing availability and interest for this positron emitter in radiopharmaceutical chemistry.

This chapter addresses this complex interdisciplinary and rapidly growing field from a radiochemist point of view, focusing on the synthesis of fluorine‐18‐labelled radiopharmaceuticals. We have tried to give the reader an extensive overview, without being exhaustive, covering the beginnings as well as the latest developments, from the production of the radioisotope and primary labelling precursors to sophisticated radiosynthetic procedures. Radiochemical yields appearing in this chapter are generally corrected for decay unless stated otherwise. Only a limited number of examples could be integrated in this text. For a more complete overview of fluorine‐18‐labelled structures we would like to draw the reader’s attention to the regularly updated website of R. Iwata, at the Cyclotron and Radioisotope Center of Tohoku University: http://kakuyaku.cyric.tohoku.ac.jp/indexe.html.

2 THE RADIONUCLIDE FLUORINE‐18 AND SOME GENERAL CONSIDERATIONS CONCERNING SHORT‐LIVED POSITRON EMITTERS

2.1 The position of fluorine‐18 among short‐lived positron emitters for PET

Carbon‐11, nitrogen‐13, oxygen‐15 and especially fluorine‐18 are the short‐lived positron‐emitting radionuclides that have had the greatest impact on PET. This is understandable in view of the fact that the first three are isotopes of basic elements of life. They can substitute their stable counterparts without changing the properties of the target organic molecule. While fluorine is not a significant element in living systems, its longer half‐life and its physico–chemical properties make it of considerable value. Table 1 lists some of the physical properties of these radionuclides, including two other radiohalogens, bromine‐76 and iodine‐124, for comparison.

Table 1

Short‐lived positron‐emitting radionuclides for PET imaging

Specific activity (SA) defined as radioactivity per unit mass.

Fluorine‐18 is an artificial radionuclide, discovered in 1937. It decays with a half‐life of 109.8 min for 97% by positron emission and for 3% by electron capture to the stable isotope oxygen‐18. The maximum β⁺‐particle energy is 0.635 MeV [4]. Compared with other positron‐emitting radiohalogens used in PET such as bromine‐76 (half‐life: 16.1 h) or iodine‐124 (half‐life: 4.18 days), fluorine‐18 displays simpler decay and emission properties with a high positron abundance [4]. As a result of its shorter half‐life and its lower positron energy, fluorine‐18‐labelled radiopharmaceuticals give a lower radiation dose to patients. Compared with the other short‐lived PET radionuclides carbon‐11, nitrogen‐13 and oxygen‐15 with equally simple decay schemes, fluorine‐18 has once more a relatively low positron energy and the shortest positron linear range in tissue (max 2.3 mm), resulting in the highest resolution in PET imaging. On the contrary, the radiation dose received by a patient exposed to the shorter‐lived carbon‐11, nitrogen‐13 or oxygen‐15 is considerably lower.

Its half‐life is long enough to give access to relatively extended imaging protocols compared with what is possible with carbon‐11. It facilitates kinetic studies and high‐quality metabolite and plasma analysis because of higher count rates and better statistics over a longer time. On the contrary, the half‐life is too long for repeated injection and imaging with the same or a different radiotracer, which is conceivable with carbon‐11, nitrogen‐13 and oxygen‐15.

From a chemical point of view, the half‐life of fluorine‐18 allows multi‐step synthetic approaches that can be extended over hours. Fluorine‐18 has therefore, in spite of its somewhat limited chemical repertoire, been effectively used for the labelling of numerous both relatively simple and complex bioactive chemical structures [3,5–9], including high‐molecular‐weight macromolecules such as peptides, proteins [10–13] and oligonucleotides [14–18]. General considerations on radiochemistry involving short‐lived positron emitters will be discussed in Section 2.3.

Finally, fluorine‐18 can be reliably and routinely produced at the multi‐Curie level [19] on widely implemented biomedical cyclotrons of relatively low‐energy proton beam (e.g. 18 MeV). This fact, combined with its favourable half‐life, permits the transport and the use of fluorine‐18‐labelled radiopharmaceuticals (such as the archetype [¹⁸F]FDG) at ‘satellite’ PET units that do not have the disposal of an on‐site cyclotron facility [20,21]. Aspects on fluorine‐18 production will be discussed in Section 2.4.

2.2 Design of radiotracers and radiopharmaceuticals labelled with a short‐lived positron emitter: The case of fluorine‐18

The design of radiotracers or radiopharmaceuticals labelled with shor...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• Part I: Molecular Imaging
• Part II: Biomedical Materials
• Part III: Pharmaceuticals
• Subject Index