Fluorine and Health (eBook)

Front Cover 1
Fluorine and Health 4
Copyright Page 5
Contents 6
Contributors 10
Preface 12
Part I: Molecular Imaging 16
Chapter 1: Fluorine-18 Chemistry for Molecular Imaging with Positron Emission Tomography 18
1. Introduction 19
2. The radionuclide fluorine-18 and some general considerations concerning short-lived positron emitters 20
2.1. The position of fluorine-18 among short-lived positron emitters for PET 20
2.2. Design of radiotracers and radiopharmaceuticals labelled with a short-lived positron emitter: The case of fluorine-18 22
2.3. Challenges in radiochemistry with short- lived. positron emitters, including fluorine-18 23
2.4. Fluorine-18 production 25
2.5. Methods of radiofluorination 26
2.6. Early fluorine-18-labelled precursors 27
3. Electrophilic radiofluorination 29
3.1. Preparation of electrophilic fluorination reagents 30
3.1.1. Molecular[18F]fluorine 30
3.1.2. Trifluoromethyl [18F]hypofluorite 30
3.1.3. Acetyl [18F]hypofluorite 30
3.1.4. Perchloryl [18F]fluoride 31
3.1.5. Xenon di[18F]fluoride 31
3.1.6. 1-[18F]Fluoro-2-pyridone 32
3.1.7. N-[18F]Fluoropyridinium triflate 32
3.1.8. N-[18F]Fluoro-N-alkylsulphonamides 32
3.1.9. Bromo [18F]fluoride 33
3.2. Fluorination of double-bond structures 33
3.2.1. Fluorination of alkenes 33
3.2.2. Fluorination of enol structures 36
3.3. Fluorination of carbanions 37
3.4. Fluorination of aromatic rings (other than via carbanions) 38
3.4.1. Fluorodehydrogenation 39
3.4.2. Fluorodemetallation 40
4. Nucleophilic radiofluorination 43
4.1. Preparation of reactive [18F]fluoride anion 43
4.2. Nucleophilic aliphatic substitution 44
4.2.1. Basic principles 44
4.2.2. Preparation of simple [18F]fluoroalkyl-type molecular building blocks and some applications 45
4.2.3. One-step synthesis of a radiopharmaceutical involving an aliphatic nucleophilic fluorination 47
4.2.4. Multi-step synthesis of a radiopharmaceutical involving an aliphatic nucleophilic fluorination 47
4.3. Nucleophilic aromatic substitution 50
4.3.1. Homoaromatic series 50
4.3.2. Heteroaromatic series 56
5. Enzymatic carbon-[18f]fluorine bond formation 58
6. The particular case of macromolecule labelling with fluorine-18 60
6.1. Reagents for the fluorine-18 labelling of peptides and proteins 60
6.2. Reagents for the fluorine-18 labelling of oligonucleotides 63
7. Conclusion and perspectives 64
References 65
Note from the Editors 80
Chapter 2: Application of 18F-PET Imaging for the Study of Alzheimer's Disease 82
1. Introduction 83
2. PET and SPECT imaging in AD 84
2.1. Special features of 18F-radiopharmaceuticals 84
2.2. Glucose metabolism and blood flow 85
2.3. Serotonergic system 87
2.4. Dopaminergic system 88
2.5. Cholinergic system 89
2.6. Histamine and benzodiazepine receptors 91
2.7. Amyloid deposits 92
3. Conclusions 93
References 94
Note from the Editors 99
Chapter 3: 18F-Labeled PET-T racers for Cardiological Imaging 100
1. Molecular imaging of the myocardium 101
1.1. Background 101
1.2. 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) 102
1.2.1. Mechanism of accumulation in myocytes 102
1.2.2. Radiosynthesis 103
1.3. Fatty acids 104
2. Molecular imaging of vessels 106
2.1. Atherosclerosis 106
2.2. Endothelin-system 109
2.3. Perfusion 111
3. Innervation 114
3.1. Sympathetic and parasympathetic innervation 114
3.2. beta-Adrenoceptors 115
3.3. 18F-labeled radioligands for PET imaging of beta-adrenoceptors 121
3.3.1. [18F]Fluoroacetone as radiolabeling building block 121
3.3.2. [18F]Fluoroisopropyl derivatives as radiolabeling building blocks 124
3.3.3. [18F]Fluoroethyl derivatives as radiolabeling building blocks 126
3.4. alpha-Adrenoceptors 128
3.5. Muscarinic acetylcholine receptors 128
3.6. Norepinephrine transporter and vesicular monoamine transporter 133
4. Summary and perspectives 140
Annex: 18F-labeled PET-tracers for cardiological imaging — update 141
Acknowledgments 142
References 143
Note from the Editors 154
Chapter 4: [18F]-Labeled PET and PET/CT Compounds in Oncology 156
1. Introduction 157
2. [18F]-FDG-PET and -PET/CT in oncology 159
2.1. Main indications of [18F]-FDG-PET and -PET/CT 159
2.1.1. Colorectal cancer 161
2.1.2. Lung cancer 168
2.1.3. Lymphoma 170
2.1.4. Breast cancer 172
2.1.5. Esophageal cancer 174
2.2. Therapy monitoring with [18F]-FDG-PET and [18F]-FDG-PET/CT 177
2.2.1. Gastrointestinal tract (GI) 178
2.2.2. Lung cancer 181
2.2.3. Lymphoma 182
2.2.4. Gastrointestinal stromal tumors (GIST) 182
2.2.5. Head and neck 183
2.2.6. Breast cancer 183
2.2.7. Ovarian cancer 183
2.3. Methodical considerations and limitations 184
3. Innovative [18F] fluorine-based radiotracers 185
3.1. Molecular imaging of proliferation with 3'-deoxy-3'-[18F]-fluorothymidine 185
3.2. PET/CT studies of tumor hypoxia 188
3.3. [18F]-Galacto-RGD-PET: Imaging of alphavbeta3 integrin expression 190
3.4. [18F]-Fluorocholine-PET: Imaging of prostate cancer 191
3.4.1. Biochemical rationale 191
3.4.2. Compounds, biodistribution, and imaging 192
3.4.3. Clinical studies 193
3.5. [18F]-Fluoride-PET: Imaging of bone metastases 193
3.6. [18F]FET-PET: Imaging with amino acids 194
3.7. [18F]Fluorodopa-PET: Imaging with amino precursors 196
Acknowledgments 197
References 197
Note from the Editors 211
Chapter 5: Non-Invasive Physiology and Pharmacology Using 19F Magnetic Resonance 212
1. Introduction 213
1.1. Context and perspective 214
1.2. 19F as an in vivo NMR probe 216
2. 19F NMR for pharmacology 230
2.1. Cancer chemotherapeutics 231
2.1.1. Fluoropyrimidines 231
2.1.2. Other anticancer drugs 232
2.2. Other drugs 233
3. Active reporter molecules 235
3.1. Physical interactions 235
3.1.1. In vivo oximetry 235
3.1.2. pH 246
3.1.3. Metal ions 250
3.1.4. Caveats 257
3.2. Chemical interactions 258
3.2.1. Metabolism of FDG 258
3.2.2. Hypoxia 259
3.2.3. Enzyme reporters 260
4. Passive reporter molecules 267
5. Potential innovations and improvements 268
6. Conclusions 268
Acknowledgments 269
References 269
Part II: Biomedical Materials 292
Chapter 6: Fluoride-Based Bioceramics 294
1. Introduction 296
2. Overview of bioceramics and related biomaterials incorporating fluoride ions 296
3. Fluorapatite and fluoridated apatites: Structure and characterisation 299
3.1. Crystal structure of stoichiometric fluorapatite 299
3.2. Substituted fluoridated apatites 301
3.3. Physico-chemical characterisation of fluoridated apatites 303
3.3.1. X-ray diffraction 303
3.3.2. FTIR spectroscopy 304
3.3.3. Solid-state NMR 305
3.3.4. Difficulties related to the characterisation of fluoridated apatites 311
4. Physico-chemical properties of fluoridated apatites 311
4.1. Dissolution properties of fluoridated apatites 311
4.2. Fluoridation reactions 312
4.3. Thermal stability 313
4.4. Thermodynamic characteristics 314
4.5. Surface characteristics 314
4.5.1. Surface energy 314
4.5.2. Surface charge 315
4.5.3. Adsorption properties 315
4.6. Fluoridation effects 315
4.7. Mechanical properties of fluoridated apatite ceramics 316
5. Fluor-containing glasses and cements 317
5.1. Fluor-containing glasses 317
5.2. Fluoridated cements 320
6. Preparation and synthesis routes of fluoride- containing apatites 321
6.1. High-temperature methods 321
6.1.1. Solid–gas reaction 321
6.1.2. Pyrolysis method 322
6.1.3. Crystal growth method 322
6.2. Low-temperature methods 323
6.2.1. Hydrolysis method 323
6.2.2. Precipitation method 323
6.2.3. Exchange and/or dissolution–reprecipitation reactions 324
6.2.4. Sol-gel method 325
6.2.5. Crystal growth method 325
7. Processing techniques for fluoride-containing bioceramics 326
7.1. Processing of massive bioceramics containing fluoride 326
7.2. Fluoride-containing bioceramic coatings 327
7.2.1. High-energy processing 327
7.2.2. Solution-mediated processing 329
8. Fluoride ions in biological apatites 331
9. Biological properties of fluoride-containing bioceramics 334
9.1. Biological properties of fluoride ions in solution 334
9.1.1. Effect of fluoride ion on mineralising cells 334
9.1.2. Effect of the fluoride ion on osteoclasts 334
9.1.3. Effect of fluoride ions on bacteria 335
9.1.4. Other alterations in biological fluids related to fluoride ions 336
9.2. Effect of fluoride-containing substrates on bone cells 336
9.2.1. Osteoblast cells 336
9.2.2. Osteoclast cells 336
10. Conclusion 337
References 337
Note from the Editors 346
Chapter 7: Fluoride in Dentistry and Dental Restoratives 348
1. Introduction 349
2. Fluoride in dentistry 350
2.1. The importance of fluoride in dental health 350
2.1.1. Fluoride in dentistry 350
2.1.2. Demineralisation/remineralisation behaviour of the tooth surface 353
2.1.3. Possible antimicrobial effect of fluoride 354
2.2. Interaction of fluoride with hydroxyapatite 355
2.2.1. Basic chemistry 355
2.2.2. Fluoride and oral health: practical aspects 358
2.3. Adverse effects of fluoride 359
2.3.1. Fluorosis 359
2.3.2. Potential systemic effects 360
3. Methods of delivering fluoride 362
3.1. Drinking water 362
3.2. Salt and milk 365
3.3. Dentifrices 366
3.4. Fluoride mouthrinses 368
3.5. Topical fluoride applications 369
3.5.1. Gels 369
3.5.2. Varnishes 370
3.6. Fluoride-releasing restorative materials 370
3.6.1. Glass-ionomers 371
3.6.2. Resin-modified glass-ionomers 376
3.6.3. Compomers 377
3.6.4. Fluoride-containing composite resins 379
4. Conclusions 380
References 381
Note from the Editors 393
Chapter 8: Fluorinated Biomaterials for Cardiovascular Surgery 394
1. Introduction 395
2. Blood-vessel wall relationships (interactions of flowing blood with the vessel/vascular prosthesis wall) 396
2.1. Role of the surface free energy or surface tension 396
2.2. Role of electrical parameters 396
2.3. Scenario for blood-material interactions 397
2.4. Role of dynamic factors 399
2.5. Role of the morphology 400
3. Requirements for a cardiovascular biomaterial 401
4. From polytetrafluoroethylene to microporous teflon-based vascular prostheses 403
4.1. State of the art related to vessel repair or replacement: Evolution and role of PTFE 404
4.2. How to improve the functional patency of ePTFE-based prostheses? 407
4.3. Chemical modifications of fluorinated polymers: A way to the improvement of their haemocompatibility 409
4.3.1. PTFE case 409
4.3.2. PVDF case 411
4.3.3. P(VDF-HFP) case 416
5. Conclusions 417
References 419
Note from the Editors 421
Chapter 9: Fluorinated Molecules in Eye Surgery: Experimental and Clinical Benefit of a Heavy Silicone Oil Oxane Hdregs (Mixture of Silicone Oil... 422
1. Introduction 422
2. State of the art 424
3. Synthesis of RMN3 427
4. Biocompatibility of RMN3 and Oxane Hdregs 428
5. Clinical study with Oxane Hdregs 430
6. Conclusion 432
References 433
Note from the Editors 435
Chapter 10: Biocompatibility of Highly Fluorinated Liquids Used in Ophthalmic Surgery 436
1. Introduction 437
1.1. Anatomy of the human eye 437
1.2. Vitreoretinal diseases 438
1.3. Vitreoretinal surgery 439
1.4. The particularity of the use of highly fluorinated liquids as ocular endotamponades 440
2. Biocompatibility 440
2.1. Perfluorooctane and perfluorodecalin 442
2.2. New ocular endotamponades 443
2.3. Biocompatibility test scheme adjusted for FCLs for ophthalmic use 446
2.3.1. Toxicological tests 446
2.3.2. Modified test procedures for FCLs 448
2.4. Evaluation of undesirable local effects of ocular endotamponades 450
2.4.1. Effects of the high density 450
2.4.2. Oxygen content 451
2.4.3. Effects based on physicochemical behaviours 451
2.4.4. Effects based on the structure 452
2.4.5. Shape of the droplet/contact angle 454
2.4.6. Effect of impurities 455
3. New developments 456
References 458
Note from the Editors 460
Chapter 11: Perfluorochemical-Based Oxygen Therapeutics, Contrast Agents, and Beyond 462
1. Introduction 463
1.1. Brief reminder of basic properties of perfluorocarbons relevant to biomedical uses 463
1.2. Perfluorocarbons: biocompatibility and environmental issues 466
2. Oxygen Transport to Tissues 467
2.1. Challenges in the development of a PFC-based oxygen carrier 469
2.2. Product development status 470
3. Improving Diagnosis 475
3.1. Development of micron-size injectable gas bubbles as contrast agents for improved us imaging 462
3.1.1. The challenges: stabilizing microbubbles 462
3.1.2. Osmotic stabilization of micron-size bubbles using a perfluorochemical 462
3.1.3. Products and status 462
3.1.4. Prospects 462
3.2. Targeted particles for molecular imaging using US and magnetic resonance 463
4. Perfluorocarbons as Drugs and Drug Delivery Systems 484
4.1. Lung ventilation 463
4.2. Lung-surfactant replacement 463
4.4. Drug and gene delivery 463
5. Surgical Aids 487
6. Research Tools for the Life Sciences 489
6.1. Abiotic tags for controlled recognition, selection, and pairing of biopolymers 489
6.2. "Abiotic " environments-"super-nonpolar " fluorous compartments for segregation and confinement 491
6.3. Tools for nanogram-scale bioassays and protein crystallization 493
7. Conclusions and Perspectives 494
References 494
Note from the Editors 494
Chapter 12: Exposure of Humans to Fluorine and Its Assessment 502
1. Introduction 503
2. Fluorine in the environment 505
2.1. Fluoride in the lithosphere 506
2.2. Fluoride in air 506
2.3. Fluoride in natural waters 507
3. Essentiality of fluoride 509
4. Adverse effects of fluoride on humans 510
4.1. Chronic toxicity 510
4.1.1. Dental or enamel fluorosis 511
4.1.2. Skeletal fluorosis 512
4.2. Acute toxicity 513
5. Bioavailability of fluoride 514
6. Absorption, metabolism and excretion of fluoride 515
6.1. Plasma fluoride 516
6.2. Tissue fluoride 516
6.3. Fluoride in placenta and foetus 517
6.4. Elimination of fluoride 517
6.4.1. Excretion via the kidneys and urine 518
6.4.2. Excretion via faeces, saliva and sweat 518
6.4.3. Excretion via breast milk 518
7. Biomarkers of fluoride exposure and their status 518
7.1. Plasma, saliva and urine as contemporary markers 519
7.2. Nails and hair as recent markers 519
7.3. Calcified tissues as historical markers 520
8. Fluoride in diet, fluoride supplements, dental products and fluoridated salt and milk 520
8.1. Drinking water and beverages 520
8.1.1. Concentration of fluoride in drinking water 520
8.1.2. Concentration of fluoride in beverages 522
8.2. Milk and baby formulas 523
8.3. Food 524
8.4. Dietary supplements 529
8.5. Dental products 529
9. Fluoride intake 530
9.1. Fluoride intake in adults 531
9.2. Fluoride intake in children 531
9.2.1. Fluoride intake from diet 536
9.2.2. Fluoride intake from fluoride-containing toothpastes 536
9.2.3. Fluoride intake from fluoride-containing supplements 544
9.2.4. Estimated total intake of fluoride in children 545
10. Analytical methods for fluorine 547
10.1. Sample pre-treatment procedures 548
10.2. Analytical methods for determining fluorine 548
10.3. Determining fluorine in specific types of materials 549
10.3.1. Fluorine in environmental media 549
10.3.2. Fluorine in biological tissues, fluids and related materials 550
10.3.3. Fluorine in fluoride supplements and dental products 550
11. Indicators for estimating requirements for fluoride 550
12. AI of fluoride 551
13. Conclusions - enough or too much fluoride? 552
Appendix: List of acronyms 554
References 554
Note from the Editors 564
Part III: Pharmaceuticals 566
Chapter 13: Biological Impacts of Fluorination: Pharmaceuticals Based on Natural Products 568
1. Introduction 569
2. Biological impact of fluorination 569
2.1. Affinity for the macromolecule target 570
2.1.1. Steric effects 571
2.1.2. Conformational changes 572
2.1.3. Dipolar interactions and electric field 572
2.1.4. Hydrogen bond 573
2.1.5. pKa of amines 576
2.1.6. Fluorous interactions 577
2.2. Absorption 578
2.2.1. Lipophilicity 578
2.2.2. pKa and solubility 579
2.3. Metabolism 581
2.3.1. Oxidative metabolism 582
2.3.2. Hydrolytic metabolism 585
2.4. Modification of the chemical reactivity: Conception of enzyme inhibitors 587
2.4.1. Analogue of substrates as inhibitor 587
2.4.2. Inhibition by stabilisation or destabilisation of intermediates of biological processes 589
2.4.3. Irreversible inhibition with based-mechanism inhibitors (suicide-substrates) 590
3. Fluorinated pharmaceuticals based on natural products 592
3.1. Nucleosides and carbohydrates 592
3.1.1. Inhibitors of the thymidylate synthase 593
3.1.2. Inhibitors of RDPR and DNA polymerase 595
3.2. Alkaloids 600
3.2.1. Vinca alkaloids 600
3.2.2. Camptothecin 602
3.3. Lignans 603
3.3.1. Podophyllotoxin 603
3.4. Anthracyclines 604
3.5. Macrolides 605
3.5.1. Erythromycin 605
3.5.2. Epothilones 606
3.6. Steroids 608
3.6.1. Corticosteroids 608
3.6.2. Fluorosteroids acting on steroid hormone receptors 615
3.6.3. Other fluorinated steroid drugs 616
3.6.4. Vitamin D3 metabolites 618
3.7. Prostanoids 621
3.8. Terpenes 623
3.8.1. Artemisinin 623
3.9. Amino acids 625
4. Conclusion 626
References 626
Chapter 14: Synthesis and Pharmacological Properties of Fluorinated Prostanoids 638
1. Introduction 639
1.1. Biosynthesis and metabolism of prostanoids 639
1.2. Physiological properties of prostanoids and their receptors 641
1.3. Historical background of fluorinated prostanoids research 643
2. PGE Derivatives 645
2.1. 13,14-dihydro-15-keto-PGE derivative 645
2.2. EP1 receptor antagonist 647
2.3. EP2 receptor agonist 650
2.4. EP4 receptor agonist 651
3. PGF derivatives 652
3.1. FP receptor agonist 652
3.2. FP receptor antagonist 656
4. PGD derivatives 657
4.1. DP receptor agonist and antagonist 657
4.2. CRTH2 receptor agonist 659
4.3. CRTH2 receptor antagonist 659
5. PGI derivatives 661
5.1. IP receptor agonist 661
6. Concluding remarks 664
Acknowledments 667
References 667
Chapter 15: Synthesis and Biochemical Evaluation of Fluorinated Monoamine Oxidase Inhibitors 676
1. Introduction 677
1.1. Amine oxidases 677
1.1.1. Monoamine oxidases (EC 1.4.3.4) 677
1.1.2. Polyamine oxidase (EC 1.4.3.4) 679
1.1.3. Semicarbazide-sensitive amine oxidases (EC 1.4.3.6) 679
1.2. Drugs targeting amine oxidases 679
1.2.1. MAO inhibitors 679
1.2.2. SSAO inhibitors 680
1.3. Fluorine in drug design 680
2. Ring-fluorinated MAO inhibitors 681
2.1. Fluorine-substituted benzylamines and 2-phenylethylamines 681
2.2. 4-Fluorotranylcypromine 684
2.3. Aryl-N-aminoethylamide derivatives, for example, Ro-41-1049 and Ro-16-6491 685
3. Aromatic side chain-fluorinated MAO and SSAO inhibitors 686
3.1. beta,beta-Difluorinated phenethylamines 687
3.2. Fluoroallylamines as irreversible MAO inhibitors 687
3.3. Haloallylamines as SSAO inhibitors 688
3.4. Allyl hydrazines as SSAO inhibitors 689
3.5. Fluorinated aryl-oxazolidinone derivatives, for example, befloxatone 689
3.6. Fluorinated 5H-indeno[1,2-c]pyridazin-5-one MAO B-selective inhibitors 690
4. Fluorinated MAO inhibitors as PET-scanning agents 691
4.1. Fluorinated amine oxidase inhibitors as PET-imaging agents in the CNS 691
4.2. 11C-Labeled MAO inhibitors 692
4.3. 18F-Labeled MAO inhibitors 692
5. Fluorinated cyclopropylamines as inhibitors of SSAO and MAO 694
5.1. Cyclopropylamines as inhibitors of SSAO and MAO 694
5.1.1. Overview of the development of cyclopropylamines as MAO inhibitors 694
5.1.2. Isozyme selectivity of cyclopropylamine MAO inhibitors 695
5.1.3. Mechanisms of inhibition 696
5.2. Effects of fluorine substitution on inhibition of SSAO by cyclopropyl amines 698
5.3. Effects of fluorine substitution on MAO inhibition 699
6. Final comments 702
Acknowledgments 703
References 703
Chapter 16: Fluoroolefin Dipeptide Isosteres: Structure, Syntheses, and Applications 714
1. Introduction 716
1.1. Peptide isosteres 716
2. Fluoroolefin dipeptide isosteres 717
2.1. Alkenes as amide bond substitutes 717
2.2. Fluoroolefins as one of the best amide bond replacements 718
2.3. Synthesis of fluoroolefin peptide isosteres 719
3. Related methods for the synthesis of alpha-fluoro-alpha,beta-unsaturated ketones 732
3.1. Conversion from trifluoromethyl ketones via Mg(0)-promoted successive double defluorination 732
3.2. Synthesis of alpha-fluoro-alpha,beta-unsaturated ketones via palladium-catalyzed cross-coupling reaction of 1-fluorovinyl halides (79) with organostannanes (80) 734
3.3. Synthesis of alpha-fluoro-alpha,beta-unsaturated ketone via allylic hydroxylation of vinyl fluoride 734
3.4. Synthesis of alpha-fluoroenone from 1,1,1,2-tetrafluoroethane 734
3.5. Miscellaneous reactions 735
4. Metathesis reactions 736
5. Biological applications and utility of fluoroolefin peptide isosteres 737
5.1. Background 737
5.1.1. Role of cis–trans geometry in biological systems 737
5.1.2. Fluorine in biological mimics 737
5.2. Peptidyl prolyl isomerases (PPIases) 738
5.2.1. Cyclophilin (CyP) inhibitors 739
5.2.2. Pin1 740
5.3. Dipeptidyl peptidase IV 740
5.3.1. DPP IV inhibition 742
5.3.2. Quiescent proline peptidase (QPP) 743
5.4. Thermolysin 743
5.5. beta-turn mimics 743
References 745
Chapter 17: Molecular Interactions of Fluorinated Amino Acids in a Native Polypeptide Environment 752
1. Introduction 753
2. Unique and versatile: The properties of fuoroalkyl groups 754
2.1. Spatial demand and steric effects 754
2.2. The electrostatic properties of the C-F bond 755
3. Effects of fluorine in protein environments: Metabolism and structural integrity 757
3.1. Proteolytic stability of Ca-fluoroalkyl amino acids 757
3.1.1. a-Chymotrypsin: A natural protein environment 757
3.1.2. Fluorine’s ambiguity: Can polar properties of fluororalkyl groups compete with conformational restrictions? 758
3.1.3. Summary 761
3.2. The "orthogonal" properties of fluoroalkyl amino acid side chains 762
3.2.1. The a-helical coiled coil: A versatile, amphiphilic model system 762
3.2.2. Fluorinated alkyl side chains in a hydrophobic environment 766
3.2.3. Fluorinated alkyl side chains in a hydrophilic environment 767
3.2.4. Summary 769
4. Conclusions and future perspectives 770
References 771
Chapter 18: Biological Fluorination in Streptomyces cattleya: The Fluorinase 776
1. Introduction 776
2. Characterisation of the fluorinase 779
3. Mechanism of the fluorinase 780
4. Reversibility of the fluorinase 783
5. The fluorinase is a chlorinase 783
6. Substrate specificity 785
7. Genetic basis of fluorination in S. cattleya 786
8. The biosynthetic pathway to fluoroacetate and 4-fluorothreonine. 787
9. The fluorinase as a tool for synthesis and formation of C-18F bonds for positron emission tomography 789
References 791
Subject Index 793
Colour Plate Section 808