Fluorine radiopharmaceuticals labeled with

The main radiopharmaceuticals labelled with fluorine-18, routinely prepared ([2-i F] fluorodeoxyglucose [ F]FDG [26-28], [i F]fluoro-L-DOPA [29], [i F]altanserin [30, 31], [ F]setoperone [32]) are presented with their uses in Table 2. For comparison, the most common tracers labelled with carbon-11 (methionine [33], palmitic acid [34], flumazenil (RO 15.1788) [35], PK 11195 [36], raclopride [37], deprenyl [38], Way-100635 [39], McN-5652Z [40], CGP 12177 [41]) are shown in Table 3. By far, [ F]FDG is the most widely studied, particularly in oncology for the diagnosis of tumours, detection of sub-clinical diseases, assessment of therapy responses, and detection of recurrence. F-Steroids [42], F-proteins or peptides, or F-labelled tissue specific agents have also been synthesized for the detection and monitoring of various malignancies [43]. 

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

Although the majority of radiopharmaceuticals labeled with fluorine-18 have been prepared using nucleophilic fluorination reactions, in a few instances the application of electrophilic fluorination reactions has proved quite suitable. The most significant limitation of electrophilic 18F-fluorinations is the relatively low specific activities (less than lOCi/mmol) commonly obtained for final products. This is a result of the fact that electrophilic 18F-fluorination reagents (perchloryl fluoride, acetyl hypofluorite, xenon difluoride, A-fluoro-zV-alkylsulfonamides, diethylaminosulfur trifluoride) are prepared in low specific activity from 18F-labeled fluorine gas, which in itself produced in a carrier-added fashion. A second drawback of electrophilic fluorination is that the maximum radiochemical yield obtainable is 50%, as only one of the two fluorine atoms in fluorine gas can end up in the product (or, for preparation of electrophilic reagents such as acetyl [18F]hypofluorite, the maximum yield of preparing the reagent from [18F]F2 is 50%). 

Whilst the work that we focus on in the first part of this chapter concerns the preparation of tritium- and inevitably deuterium-labeled compounds, examples are given where the benefits can also be applied to the carbon ( C, and C)-labeled area [8]. Also discussed is the use of microwaves in the synthesis of radiopharmaceuticals labeled with positron emitters, such as carbon-11 (ti/2 = 20.4 min) and fluorine-18 (ti/2 = 109.7 min). The short half lives of these radioisotopes, together with the requirements for high radiochemical yield (RCY), radiochemical purity (RCP) and specific activity (SA) can benefit from the advantages that micro-waves provide [8, 9]. 

E. J. Knust, H.J. Machulla, C. Astfalk, Radiopharmaceuticals V F-Labeling with water target produced fluorine-18—Synthesis and quality control of 6- F-nicotinic acid diethylamide, Radiochem. Radioanal. Lett. 55 (1983) 249-255. 

A series of fluorine-18 labelled 1,2-diazabenzenes 6 have been synthesized28 in the reaction of high specific activity, NCA [18F]fluoride ion with various chloro-substituted pyridazines 7 (equation 8) in radiochemical yields ranging from 11 to 64% [24% yield for R = Me, 64% for R = 4-benzoyl, 11% for R = 4-fluorobenzoyl, 46% for R = (2-thienyl) carbonyl]. The rat biodistribution of pyridazine analogues, more polar than the corresponding phenyl derivatives, has been studied and their applications to radiopharmaceuticals are underway28. 

Aliphatic and aromatic nucleophilic substitutions with p Fjfluoride are usually performed either on an immediate precursor of the target molecule (direct labelling using a one-step process) or on an indirect precursor followed by one or more chemical steps leading to the target radiotracer. The first approach, if highly desirable, is in fact rarely practicable. The reaction conditions are often not compatible with the structure or with the various chemical functions borne by the radiopharmaceutical. It is therefore common that the radiosynthesis comprises at least two chemical steps first the introduction of fluorine-18 followed by what is often a (multi)deprotection step. It is not unusual either that fluorine-18 is first incorporated into a much simpler and chemically more robust molecule which is then coupled to a more sensitive entity under milder conditions, possibly still followed by a final deprotection step. Suchlike multi-step procedures are possible thanks to the favourable half-life of fluorine-18. However, the more complicated the process, the more chance of side reactions and complicated final purifications (see also Section 2.3), which may seriously hamper the automation of the process. 

Some Positron Emitters of Clinical Interest Fluorine-18 is undoubtedly the most widely used positron-emitting radionuclide. This is mainly due to the wide use of 18FDG, the PET radiopharmaceutical that has permitted PET to become an everyday clinical tool. With the exception of 18FDG and probably 18FDOPA, the use of other 18F-labeled radiopharmaceuticals is very limited. However, the chemical and physical characteristics of 18F are excellent ... 

For the synthesis of high-specific-activity radiopharmaceuticals (specific activity is defined as radioactivity per unit mass) the use of [18F]fluoride ion is preferred if not required. The theoretical specific activity for fluorine-18 is 1.71 x 109Ci/mol, but that value has never been achieved and in practice the specific activity of 18F-labeled radiochemicals has been significantly lower. Typically, finished radiochemicals are produced with specific activities in the 1000-10 000 Ci/mmol. Some of this difference has been attributed to physical dilution of the fluorine-18 by the presence of fluorine-19 in... 

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