Fluorine and Health - Molecular Imaging, Biomedical Materials and Pharmaceuticals

Front Cover

Fluorine and Health

Copyright Page

Contents

Contributors

Preface

Part I: Molecular Imaging

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

1. Introduction

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

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

2.3. Challenges in radiochemistry with short- lived. positron emitters, including fluorine-18

2.4. Fluorine-18 production

2.5. Methods of radiofluorination

2.6. Early fluorine-18-labelled precursors

3. Electrophilic radiofluorination

3.1. Preparation of electrophilic fluorination reagents

3.1.1. Molecular[18F]fluorine

3.1.2. Trifluoromethyl [18F]hypofluorite

3.1.3. Acetyl [18F]hypofluorite

3.1.4. Perchloryl [18F]fluoride

3.1.5. Xenon di[18F]fluoride

3.1.6. 1-[18F]Fluoro-2-pyridone

3.1.7. N-[18F]Fluoropyridinium triflate

3.1.8. N-[18F]Fluoro-N-alkylsulphonamides

3.1.9. Bromo [18F]fluoride

3.2. Fluorination of double-bond structures

3.2.1. Fluorination of alkenes

3.2.2. Fluorination of enol structures

3.3. Fluorination of carbanions

3.4. Fluorination of aromatic rings (other than via carbanions)

3.4.1. Fluorodehydrogenation

3.4.2. Fluorodemetallation

4. Nucleophilic radiofluorination

4.1. Preparation of reactive [18F]fluoride anion

4.2. Nucleophilic aliphatic substitution

4.2.1. Basic principles

4.2.2. Preparation of simple [18F]fluoroalkyl-type molecular building blocks and some applications

4.2.3. One-step synthesis of a radiopharmaceutical involving an aliphatic nucleophilic fluorination

4.2.4. Multi-step synthesis of a radiopharmaceutical involving an aliphatic nucleophilic fluorination

4.3. Nucleophilic aromatic substitution

4.3.1. Homoaromatic series

4.3.2. Heteroaromatic series

5. Enzymatic carbon-[18f]fluorine bond formation

6. The particular case of macromolecule labelling with fluorine-18

6.1. Reagents for the fluorine-18 labelling of peptides and proteins

6.2. Reagents for the fluorine-18 labelling of oligonucleotides

7. Conclusion and perspectives

References

Note from the Editors

Chapter 2: Application of 18F-PET Imaging for the Study of Alzheimer's Disease

1. Introduction

2. PET and SPECT imaging in AD

2.1. Special features of 18F-radiopharmaceuticals

2.2. Glucose metabolism and blood flow

2.3. Serotonergic system

2.4. Dopaminergic system

2.5. Cholinergic system

2.6. Histamine and benzodiazepine receptors

2.7. Amyloid deposits

3. Conclusions

References

Note from the Editors

Chapter 3: 18F-Labeled PET-T racers for Cardiological Imaging

1. Molecular imaging of the myocardium

1.1. Background

1.2. 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG)

1.2.1. Mechanism of accumulation in myocytes

1.2.2. Radiosynthesis

1.3. Fatty acids

2. Molecular imaging of vessels

2.1. Atherosclerosis

2.2. Endothelin-system

2.3. Perfusion

3. Innervation

3.1. Sympathetic and parasympathetic innervation

3.2. beta-Adrenoceptors

3.3. 18F-labeled radioligands for PET imaging of beta-adrenoceptors

3.3.1. [18F]Fluoroacetone as radiolabeling building block

3.3.2. [18F]Fluoroisopropyl derivatives as radiolabeling building blocks

3.3.3. [18F]Fluoroethyl derivatives as radiolabeling building blocks

3.4. alpha-Adrenoceptors

3.5. Muscarinic acetylcholine receptors

3.6. Norepinephrine transporter and vesicular monoamine transporter

4. Summary and perspectives

Annex: 18F-labeled PET-tracers for cardiological imaging — update

Acknowledgments

References

Note from the Editors

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

1. Introduction

2. [18F]-FDG-PET and -PET/CT in oncology

2.1. Main indications of [18F]-FDG-PET and -PET/CT

2.1.1. Colorectal cancer

2.1.2. Lung cancer

2.1.3. Lymphoma

2.1.4. Breast cancer

2.1.5. Esophageal cancer

2.2. Therapy monitoring with [18F]-FDG-PET and [18F]-FDG-PET/CT

2.2.1. Gastrointestinal tract (GI)

2.2.2. Lung cancer

2.2.3. Lymphoma

2.2.4. Gastrointestinal stromal tumors (GIST)

2.2.5. Head and neck

2.2.6. Breast cancer

2.2.7. Ovarian cancer

2.3. Methodical considerations and limitations

3. Innovative [18F] fluorine-based radiotracers

3.1. Molecular imaging of proliferation with 3'-deoxy-3'-[18F]-fluorothymidine

3.2. PET/CT studies of tumor hypoxia

3.3. [18F]-Galacto-RGD-PET: Imaging of alphavbeta3 integrin expression

3.4. [18F]-Fluorocholine-PET: Imaging of prostate cancer

3.4.1. Biochemical rationale

3.4.2. Compounds, biodistribution, and imaging

3.4.3. Clinical studies

3.5. [18F]-Fluoride-PET: Imaging of bone metastases

3.6. [18F]FET-PET: Imaging with amino acids

3.7. [18F]Fluorodopa-PET: Imaging with amino precursors

Acknowledgments

References

Note from the Editors

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

1. Introduction

1.1. Context and perspective

1.2. 19F as an in vivo NMR probe

2. 19F NMR for pharmacology

2.1. Cancer chemotherapeutics

2.1.1. Fluoropyrimidines

2.1.2. Other anticancer drugs

2.2. Other drugs

3. Active reporter molecules

3.1. Physical interactions

3.1.1. In vivo oximetry

3.1.2. pH

3.1.3. Metal ions

3.1.4. Caveats

3.2. Chemical interactions

3.2.1. Metabolism of FDG

3.2.2. Hypoxia

3.2.3. Enzyme reporters

4. Passive reporter molecules

5. Potential innovations and improvements

6. Conclusions

Acknowledgments

References

Part II: Biomedical Materials

Chapter 6: Fluoride-Based Bioceramics

1. Introduction

2. Overview of bioceramics and related biomaterials incorporating fluoride ions

3. Fluorapatite and fluoridated apatites: Structure and characterisation

3.1. Crystal structure of stoichiometric fluorapatite

3.2. Substituted fluoridated apatites

3.3. Physico-chemical characterisation of fluoridated apatites

3.3.1. X-ray diffraction

3.3.2. FTIR spectroscopy

3.3.3. Solid-state NMR

3.3.4. Difficulties related to the characterisation of fluoridated apatites

4. Physico-chemical properties of fluoridated apatites

4.1. Dissolution properties of fluoridated apatites

4.2. Fluoridation reactions

4.3. Thermal stability

4.4. Thermodynamic characteristics

4.5. Surface characteristics

4.5.1. Surface energy

4.5.2. Surface charge

4.5.3. Adsorption properties

4.6. Fluoridation effects

4.7. Mechanical properties of fluoridated apatite ceramics

5. Fluor-containing glasses and cements

5.1. Fluor-containing glasses

5.2. Fluoridated cements

6. Preparation and synthesis routes of fluoride- containing apatites

6.1. High-temperature methods

6.1.1. Solid–gas reaction

6.1.2. Pyrolysis method

6.1.3. Crystal growth method

6.2. Low-temperature methods

6.2.1. Hydrolysis method

6.2.2. Precipitation method

6.2.3. Exchange and/or dissolution–reprecipitation reactions

6.2.4. Sol-gel method

6.2.5. Crystal growth method

7. Processing techniques for fluoride-containing bioceramics

7.1. Processing of massive bioceramics containing fluoride

7.2. Fluoride-containing bioceramic coatings

7.2.1. High-energy processing

7.2.2. Solution-mediated processing

8. Fluoride ions in biological apatites

9. Biological properties of fluoride-containing bioceramics

9.1. Biological properties of fluoride ions in solution

9.1.1. Effect of fluoride ion on mineralising cells

9.1.2. Effect of the fluoride ion on osteoclasts

9.1.3. Effect of fluoride ions on bacteria

9.1.4. Other alterations in biological fluids related to fluoride ions

9.2. Effect of fluoride-containing substrates on bone cells

9.2.1. Osteoblast cells

9.2.2. Osteoclast cells

10. Conclusion

References

Note from the Editors

Chapter 7: Fluoride in Dentistry and Dental Restoratives

1. Introduction

2. Fluoride in dentistry

2.1. The importance of fluoride in dental health

2.1.1. Fluoride in dentistry

2.1.2. Demineralisation/remineralisation behaviour of the tooth surface

2.1.3. Possible antimicrobial effect of fluoride

2.2. Interaction of fluoride with hydroxyapatite

2.2.1. Basic chemistry

2.2.2. Fluoride and oral health: practical aspects

2.3. Adverse effects of fluoride

2.3.1. Fluorosis

2.3.2. Potential systemic effects

3. Methods of delivering fluoride

3.1. Drinking water

3.2. Salt and milk

3.3. Dentifrices

3.4. Fluoride mouthrinses

3.5. Topical fluoride applications

3.5.1. Gels

3.5.2. Varnishes

3.6. Fluoride-releasing restorative materials

3.6.1. Glass-ionomers

3.6.2. Resin-modified glass-ionomers

3.6.3. Compomers

3.6.4. Fluoride-containing composite resins

4. Conclusions

References

Note from the Editors

Chapter 8: Fluorinated Biomaterials for Cardiovascular Surgery

1. Introduction

2. Blood-vessel wall relationships (interactions of flowing blood with the vessel/vascular prosthesis wall)

2.1. Role of the surface free energy or surface tension

2.2. Role of electrical parameters

2.3. Scenario for blood-material interactions

2.4. Role of dynamic factors

2.5. Role of the morphology

3. Requirements for a cardiovascular biomaterial

4. From polytetrafluoroethylene to microporous teflon-based vascular prostheses

4.1. State of the art related to vessel repair or replacement: Evolution and role of PTFE

4.2. How to improve the functional patency of ePTFE-based prostheses?

4.3. Chemical modifications of fluorinated polymers: A way to the improvement of their haemocompatibility

4.3.1. PTFE case

4.3.2. PVDF case

4.3.3. P(VDF-HFP) case

5. Conclusions

References

Note from the Editors

Chapter 9: Fluorinated Molecules in Eye Surgery: Experimental and Clinical Benefit of a Heavy Silicone Oil Oxane Hdregs (Mixture of Silicone Oil...

1. Introduction

2. State of the art

3. Synthesis of RMN3

4. Biocompatibility of RMN3 and Oxane Hdregs

5. Clinical study with Oxane Hdregs

6. Conclusion

References

Note from the Editors

Chapter 10: Biocompatibility of Highly Fluorinated Liquids Used in Ophthalmic Surgery

1. Introduction

1.1. Anatomy of the human eye

1.2. Vitreoretinal diseases

1.3. Vitreoretinal surgery

1.4. The particularity of the use of highly fluorinated liquids as ocular endotamponades

2. Biocompatibility

2.1. Perfluorooctane and perfluorodecalin

2.2. New ocular endotamponades

2.3. Biocompatibility test scheme adjusted for FCLs for ophthalmic use

2.3.1. Toxicological tests

2.3.2. Modified test procedures for FCLs

2.4. Evaluation of undesirable local effects of ocular endotamponades

2.4.1. Effects of the high density

2.4.2. Oxygen content

2.4.3. Effects based on physicochemical behaviours

2.4.4. Effects based on the structure

2.4.5. Shape of the droplet/contact angle

2.4.6. Effect of impurities

3. New developments

References

Note from the Editors

Chapter 11: Perfluorochemical-Based Oxygen Therapeutics, Contrast Agents, and Beyond

1. Introduction

1.1. Brief reminder of basic properties of perfluorocarbons relevant to biomedical uses

1.2. Perfluorocarbons: biocompatibility and environmental issues

2. Oxygen Transport to Tissues

2.1. Challenges in the development of a PFC-based oxygen carrier

2.2. Product development status

3. Improving Diagnosis

3.1. Development of micron-size injectable gas bubbles as contrast agents for improved us imaging

3.1.1. The challenges: stabilizing microbubbles

3.1.2. Osmotic stabilization of micron-size bubbles using a perfluorochemical

3.1.3. Products and status

3.1.4. Prospects

3.2. Targeted particles for molecular imaging using US and magnetic resonance

4. Perfluorocarbons as Drugs and Drug Delivery Systems

4.1. Lung ventilation

4.2. Lung-surfactant replacement

4.4. Drug and gene delivery

5. Surgical Aids

6. Research Tools for the Life Sciences

6.1. Abiotic tags for controlled recognition, selection, and pairing of biopolymers

6.2. "Abiotic " environments-"super-nonpolar " fluorous compartments for segregation and confinement

6.3. Tools for nanogram-scale bioassays and protein crystallization

7. Conclusions and Perspectives

References

Note from the Editors

Chapter 12: Exposure of Humans to Fluorine and Its Assessment

1. Introduction

2. Fluorine in the environment

2.1. Fluoride in the lithosphere

2.2. Fluoride in air

2.3. Fluoride in natural waters

3. Essentiality of fluoride

4. Adverse effects of fluoride on humans

4.1. Chronic toxicity

4.1.1. Dental or enamel fluorosis

4.1.2. Skeletal fluorosis

4.2. Acute toxicity

5. Bioavailability of fluoride

6. Absorption, metabolism and excretion of fluoride

6.1. Plasma fluoride

6.2. Tissue fluoride

6.3. Fluoride in placenta and foetus

6.4. Elimination of fluoride

6.4.1. Excretion via the kidneys and urine

6.4.2. Excretion via faeces, saliva and sweat

6.4.3. Excretion via breast milk

7. Biomarkers of fluoride exposure and their status

7.1. Plasma, saliva and urine as contemporary markers

7.2. Nails and hair as recent markers

7.3. Calcified tissues as historical markers

8. Fluoride in diet, fluoride supplements, dental products and fluoridated salt and milk

8.1. Drinking water and beverages

8.1.1. Concentration of fluoride in drinking water

8.1.2. Concentration of fluoride in beverages

8.2. Milk and baby formulas

8.3. Food

8.4. Dietary supplements

8.5. Dental products

9. Fluoride intake

9.1. Fluoride intake in adults

9.2. Fluoride intake in children

9.2.1. Fluoride intake from diet

9.2.2. Fluoride intake from fluoride-containing toothpastes

9.2.3. Fluoride intake from fluoride-containing supplements

9.2.4. Estimated total intake of fluoride in children

10. Analytical methods for fluorine

10.1. Sample pre-treatment procedures

10.2. Analytical methods for determining fluorine

10.3. Determining fluorine in specific types of materials

10.3.1. Fluorine in environmental media

10.3.2. Fluorine in biological tissues, fluids and related materials

10.3.3. Fluorine in fluoride supplements and dental products

11. Indicators for estimating requirements for fluoride

12. AI of fluoride

13. Conclusions - enough or too much fluoride?

Appendix: List of acronyms

References

Note from the Editors

Part III: Pharmaceuticals

Chapter 13: Biological Impacts of Fluorination: Pharmaceuticals Based on Natural Products

1. Introduction

2. Biological impact of fluorination

2.1. Affinity for the macromolecule target

2.1.1. Steric effects

2.1.2. Conformational changes

2.1.3. Dipolar interactions and electric field

2.1.4. Hydrogen bond

2.1.5. pKa of amines

2.1.6. Fluorous interactions

2.2. Absorption

2.2.1. Lipophilicity

2.2.2. pKa and solubility

2.3. Metabolism

2.3.1. Oxidative metabolism

2.3.2. Hydrolytic metabolism

2.4. Modification of the chemical reactivity: Conception of enzyme inhibitors

2.4.1. Analogue of substrates as inhibitor

2.4.2. Inhibition by stabilisation or destabilisation of intermediates of biological processes

2.4.3. Irreversible inhibition with based-mechanism inhibitors (suicide-substrates)

3. Fluorinated pharmaceuticals based on natural products

3.1. Nucleosides and carbohydrates

3.1.1. Inhibitors of the thymidylate synthase

3.1.2. Inhibitors of RDPR and DNA polymerase

3.2. Alkaloids

3.2.1. Vinca alkaloids

3.2.2. Camptothecin

3.3. Lignans

3.3.1. Podophyllotoxin

3.4. Anthracyclines

3.5. Macrolides

3.5.1. Erythromycin

3.5.2. Epothilones

3.6. Steroids

3.6.1. Corticosteroids

3.6.2. Fluorosteroids acting on steroid hormone receptors

3.6.3. Other fluorinated steroid drugs

3.6.4. Vitamin D3 metabolites

3.7. Prostanoids

3.8. Terpenes

3.8.1. Artemisinin

3.9. Amino acids

4. Conclusion

References

Chapter 14: Synthesis and Pharmacological Properties of Fluorinated Prostanoids

1. Introduction

1.1. Biosynthesis and metabolism of prostanoids

1.2. Physiological properties of prostanoids and their receptors

1.3. Historical background of fluorinated prostanoids research

2. PGE Derivatives

2.1. 13,14-dihydro-15-keto-PGE derivative

2.2. EP1 receptor antagonist

2.3. EP2 receptor agonist

2.4. EP4 receptor agonist

3. PGF derivatives

3.1. FP receptor agonist

3.2. FP receptor antagonist

4. PGD derivatives

4.1. DP receptor agonist and antagonist

4.2. CRTH2 receptor agonist

4.3. CRTH2 receptor antagonist

5. PGI derivatives

5.1. IP receptor agonist

6. Concluding remarks

Acknowledments

References

Chapter 15: Synthesis and Biochemical Evaluation of Fluorinated Monoamine Oxidase Inhibitors

1. Introduction

1.1. Amine oxidases

1.1.1. Monoamine oxidases (EC 1.4.3.4)

1.1.2. Polyamine oxidase (EC 1.4.3.4)

1.1.3. Semicarbazide-sensitive amine oxidases (EC 1.4.3.6)

1.2. Drugs targeting amine oxidases

1.2.1. MAO inhibitors

1.2.2. SSAO inhibitors

1.3. Fluorine in drug design

2. Ring-fluorinated MAO inhibitors

2.1. Fluorine-substituted benzylamines and 2-phenylethylamines

2.2. 4-Fluorotranylcypromine

2.3. Aryl-N-aminoethylamide derivatives, for example, Ro-41-1049 and Ro-16-6491

3. Aromatic side chain-fluorinated MAO and SSAO inhibitors

3.1. beta,beta-Difluorinated phenethylamines

3.2. Fluoroallylamines as irreversible MAO inhibitors

3.3. Haloallylamines as SSAO inhibitors

3.4. Allyl hydrazines as SSAO inhibitors

3.5. Fluorinated aryl-oxazolidinone derivatives, for example, befloxatone

3.6. Fluorinated 5H-indeno[1,2-c]pyridazin-5-one MAO B-selective inhibitors

4. Fluorinated MAO inhibitors as PET-scanning agents

4.1. Fluorinated amine oxidase inhibitors as PET-imaging agents in the CNS

4.2. 11C-Labeled MAO inhibitors

4.3. 18F-Labeled MAO inhibitors

5. Fluorinated cyclopropylamines as inhibitors of SSAO and MAO

5.1. Cyclopropylamines as inhibitors of SSAO and MAO

5.1.1. Overview of the development of cyclopropylamines as MAO inhibitors

5.1.2. Isozyme selectivity of cyclopropylamine MAO inhibitors

5.1.3. Mechanisms of inhibition

5.2. Effects of fluorine substitution on inhibition of SSAO by cyclopropyl amines

5.3. Effects of fluorine substitution on MAO inhibition

6. Final comments

Acknowledgments

References

Chapter 16: Fluoroolefin Dipeptide Isosteres: Structure, Syntheses, and Applications

1. Introduction

1.1. Peptide isosteres

2. Fluoroolefin dipeptide isosteres

2.1. Alkenes as amide bond substitutes

2.2. Fluoroolefins as one of the best amide bond replacements

2.3. Synthesis of fluoroolefin peptide isosteres

3. Related methods for the synthesis of alpha-fluoro-alpha,beta-unsaturated ketones

3.1. Conversion from trifluoromethyl ketones via Mg(0)-promoted successive double defluorination

3.2. Synthesis of alpha-fluoro-alpha,beta-unsaturated ketones via palladium-catalyzed cross-coupling reaction of 1-fluorovinyl halides (79) with organostannanes (80)

3.3. Synthesis of alpha-fluoro-alpha,beta-unsaturated ketone via allylic hydroxylation of vinyl fluoride

3.4. Synthesis of alpha-fluoroenone from 1,1,1,2-tetrafluoroethane

3.5. Miscellaneous reactions

4. Metathesis reactions

5. Biological applications and utility of fluoroolefin peptide isosteres

5.1. Background

5.1.1. Role of cis–trans geometry in biological systems

5.1.2. Fluorine in biological mimics

5.2. Peptidyl prolyl isomerases (PPIases)

5.2.1. Cyclophilin (CyP) inhibitors

5.2.2. Pin1

5.3. Dipeptidyl peptidase IV

5.3.1. DPP IV inhibition

5.3.2. Quiescent proline peptidase (QPP)

5.4. Thermolysin

5.5. beta-turn mimics

References

Chapter 17: Molecular Interactions of Fluorinated Amino Acids in a Native Polypeptide Environment

1. Introduction

2. Unique and versatile: The properties of fuoroalkyl groups

2.1. Spatial demand and steric effects

2.2. The electrostatic properties of the C-F bond

3. Effects of fluorine in protein environments: Metabolism and structural integrity

3.1. Proteolytic stability of Ca-fluoroalkyl amino acids

3.1.1. a-Chymotrypsin: A natural protein environment

3.1.2. Fluorine’s ambiguity: Can polar properties of fluororalkyl groups compete with conformational restrictions?

3.1.3. Summary

3.2. The "orthogonal" properties of fluoroalkyl amino acid side chains

3.2.1. The a-helical coiled coil: A versatile, amphiphilic model system

3.2.2. Fluorinated alkyl side chains in a hydrophobic environment

3.2.3. Fluorinated alkyl side chains in a hydrophilic environment

3.2.4. Summary

4. Conclusions and future perspectives

References

Chapter 18: Biological Fluorination in Streptomyces cattleya: The Fluorinase

1. Introduction

2. Characterisation of the fluorinase

3. Mechanism of the fluorinase

4. Reversibility of the fluorinase

5. The fluorinase is a chlorinase

6. Substrate specificity

7. Genetic basis of fluorination in S. cattleya

8. The biosynthetic pathway to fluoroacetate and 4-fluorothreonine.

9. The fluorinase as a tool for synthesis and formation of C-18F bonds for positron emission tomography

References

Subject Index

Colour Plate Section