Fluorine-18 Labelled Compounds
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I fluoríne-18 labelled compounds 3 rM. lá i I •'•$ i 3 ;? 7Í5 %• 2! % tekeningen J.R. Eykenduyn, L.F. van Rooij en E. Zeeman I fotografisch werk W.C. van Sijpveld 'i'l r. English proofreader Scott Rollins P typewerk Stance Mulders I ODslagontwerp G.J. Lijnzaad VRIJE UNIVERSITEIT TE AMSTERDAM fluorine-18 labelled compounds ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor in de wiskunde en natuurwetenschappen aan de Vrije Universiteit te Amsterdam, •I op gezag van de conrector dr. H. Verheul, hoogleraar in de faculteit der wiskunde en natuurwetenschappen, in het openbaar te veYdedigen I op vrijdag 17 maart 1978 te 15.30 uur ¡n het hoofdgebouw der universiteit, De Boelelaan 1105 doos- Jacob Pieter de Kleijn geboren te '»Gravenhage i I 1978 Centrale Reproductie Dienst Vrije Universiteit I ¿rC--''&¿ Promotor : Dr. B.van Zanten Coreferent: Prof.dr. M.G.WoWring Í1 I 1 if I- 5- I I 1 I /nuil^ ti-. s -if I V5| ^!.ia^^^ STELLINGEN I De op papier aantrekkelijke methode van 'general labelling' van organische verbindingen door middel van de reactie met 14CO¿ in aanwezigheid van mag- nesium onder invloed van 7-straling verdient een serieuze experimentele aan- pak. J. P. H. Brown. Int. J. Appl. Rad. Isot. 27. 719 (1976). II Het verdient aanbeveling dat bij dierexperimenten waarbij radiofarmaca wor- den toegediend, de activiteitsaccumulatie in een orgaan wordt beschreven in samenhang met het gewicht van het betreffende orgaan. R.P. Spencer, J.Nucl.Med. 17.1110(1976). Ill De omzetting: benzaldehyde + magnesium -*• benzit -1- magnesiumhydride is slechts waarschijnlijk onder katalyserende reactie-omstandigheden. M. Givelet. C. R. Acad. Sc, Série C 1968.881. IV Hoge kosten verbonden met de afvoer van radioactief afval van nuclidenlabo- ratoria vormen indirect een bedreiging voor het milieu. De methode der dynamische lichtverstrooiing ter bepaling van diffusiecoëffi- ciënten van macromoleculen wordt niet gediend door het mathematisch ver- hullen van onzorgvuldig experimenteren. C. T. Meneely, D. F. Edwards en R. L. Rimsay, Appl. Opties 14, 2129(1975). VI 1 Het plaatsen van verkeerslichten om uitsluitend het onderlinge fietsersverkeer I te rege!sn, ontkent ten onrechte het vreedzame en vriendelijke karakter van s fietsers. Í Amsterdam, 17 maart 1978 J. P. de Kleijn CONTENTS Chapter I. INTRODUCTION« 9 1.1 The beginning. 9 1.2 Radiopharmaceuticals. 10 1.3 Fluorine-I8. 12 1.4 References. 13 Chapter II. ORGANIC SYNTHESIS WITH FLUORINE-18. 15 A LITERATURE SURVEY. 2.1 Introduction. 15 2.2 References. 16 2.3 Review. 17 Chapter III. LABELLING WITH REACTOR-PRODUCED FLUORINE-18. 27 3.1 Introduction. 27 3.2 References. 29 i 3.3 The Paper Chromatographie Behaviour of Reactor- Produced Fluorine-18. 29 18 3.4 K F from Reactor-Produced Fluorine-18. Synthesis 18. of Ethyl 2-Fluoropropionate- F and 4-Toluenesulfonyl Fluoride-18F. 35 I 3.5 TétraethylansDonium Fluoride-18 F. as a Fluorinating Agent. 40 1 D 3.6 Polymer Supported F as a Fluorinated Agent. 45 3 Chapter IV. I8F-LABELLED FLUORO AMINO ACIDS. 49 4.1 Introduction. 49 f-'. 18 4.2 F-labelled fluoro amino acids. 50 I 18 4.2.1 3-Fluoroalanine- F. 53 1 'i •it ^¿^ali¿ílSJí^í^ií.^ító^¿^^^ A.2.2 4-Fluoroglutainic Acid- F. 58 4.2.3 TranB-4-fluoroproline- F. 62 4.2.A Experimental. 63 4.3 References. 67 Appendix A. Some Attempts to Find Other F-Labelling Routes. 70 A.I The Conversion ROH * RF. 70 A.I.I (C H ) »ICF CHCIF. 71 2 5 2 2 IS- A.1.2 70% HF/Fyridine. 72 i A.2 The Conversion Ar-COF-»- Ar-F. 73 A. 3 References. 74 Appendix B. 1^-Radiometrie Determination of the Fluoride Content of an Anion Exchange Resin in the Fluoride Form. 75 Appendix C. The Fluoride Content of an Anion Exchange Resin 18 in the Fluoride Form. Determination Using F as a Tracer. 79 I SUMMARY. 83 SAMENVATTING. 84 1 CHAPTER I Introduction "...lea experiences que j'avais êtê conduit â faire pour mettre en evidence les radiations invisibles émises par certains corps phosphoresaents, radiations qui traversent divers corps opaques pour la lumière..." if 1.1 The beginning. The discovery of radioactivity by Henri Becquerel in 1896 introduced a new dimension into science. This only became fully recognized after the first production of artificial radionudides by Joliot and Curie in 1934. Since then this tool bas assumed a widespread application in nearly every J field of science, including medicine. 1 Today, nuclear medicine which may be defined as the application of ï~:~ radionuclide techniques in the investigation of human disease, is a rapidly expanding specialty . The foundation and essential rationale of nuclear medicine stem from ã the Hungarian chemist Von HeveBy's realization that "...radio-elements are throughout in all chemical properties exactly similar to some of tlie common elements'.'. He visualized that a radioactive atom might be used as "an in- dicator of the bodies from which they are known to be non-separable" . ft 10 For the development of the tracer methodology he had been awarded the Nobel Prise for Chemistry in 1943. Although radium is hardly an appropriate material for the study of human physiology, some intrepid clinicians already were injecting radium into the bloodstream, achieving in this way the first medical application of radioactive material in 1914 • Major boosts to the growth of nuclear medicine were the advent of nucle&r reactors (low cost and great abundance of radionuclides available) and the development of the Anger isotope camera (gamna camera). With this imaging device large interior regions of the body can be visualised in one field of view, to study movement of the radioactivity in space and time. 6,7 1.2 Radiopharmaceuticals A radiopharmaceutical is a medicinal product, generally used in the investigation of human disease, which contains a radionuclide as an integral part of the main ingredient. It is designed to be organ or function specific, that is, there is an intended "target" within the subject. A proper obser- vation of this target implies a high target-non-target ratio. This .demand requires a radiopharmaceutical design based on a thorough knowledge of the biochemical and physiological aspects involved. Generally such small quantities of the radiodiagnostic agent are administered in vivo that no physiological, biochemical or pharmacological effects are induced. Yet it is possible to measure the time-dependent dis- tribution of the agent if a radioactive label is used whose decay characteris- tics allow external monitoring. This means that studies can be performed in a non-invasive manner. The development of imaging devices and of specific radiopharmaceuticals in the last 10 years allows one to evaluate the morphol- ogy and/or function of many more organs and body regions than ever before. The application of radiopharmaceuticals in diagnostic and metabolic II studies requires not only that the radiation dose be minimal but also that the physiological pertubation be minimal. Regarding the latter the limiting factor is the size of the body "pool" of the pharmaceutical in which mixing with the unlabelled substance is assumed to occur. These "pools" may not correspond to anatomic spaces within the body but are useful as mere physio- logical concepts in understanding how the body handles these materials. A small body "pool" of a given substance may cause a noticeable loading dose Ä*> 11 effect .In such a case a rsdiopharmaceutical of high specific activity is required. The highest specific activity is connected with the carrier-free state, which in fact cannot be attained. The presence of traces of carrier in production and procedure systems always lower'the theoretical specific activity. For that reason the term "carrier-free" should be replaced by the term "no added carrier", if that is the case. From the point of view of radiation safety in relation to the patient, the personnel at the production and medical sites, and to the environment, 12 short-lived radionuclides are preferable. Wagner pointed out that the op- timal physical half-life of the nuclide incorporated in a substance used to study a physiological phenomenon in a living organism, is about 0.7 times the elapsed time between administration and measurement., He based his cal- culation on the condition of maximum information (in the form of high count- ing rates) in relation to the smallest radiation dose absorbed by the pa- tient. Wagner neglected the influence of the biological half-life of the substance which may allow the administration of a longer-lived radionuclide. As in most medical applications the waiting time is less than a few hours, fluorine-18 (ü -emitter, half-life 110 min) seems to be a very suitable radio- nuclide in this respect- Ü Imaging devices for the measurement of annihilation coincidence i ovents are being developed as a consequence of the growing interest in radio- 12 Pharmaceuticals labelled with short-lived radionuclides which decay by positron emission (e.g. HC, I3N, l50, I8F, 52Fe. 68Ga, 8!Rb). It has recent- ly been shown that positron emission transaxial reconstruction tomography is possible • fr. 1.3 Fluorine-18. Two types of labelling of naturally occurring compounds can be distinguished. First, genuine labelling with carbon, nitrogen, and oxygen isotopes which implies maintenance of the chemical integrity. Secondly, foreign labelling which yields an altered chemical product. F-labelling is mostly foreign labelling because naturally occuring fluorocompounds 14 are rare . In order to minimize the influence of the fluorination on the bio- logical activity of the compound two requirements have to be met: (a) substitution at a metabolically non-active site of the molecule, (b) F-for-H (spacial similarity) or F-for-OB (similarity in bond strength and electronegativity) substitution .