18F-labeled compounds

The incorporation of a fluorine-18 label can also be achieved by standard aliphatic nucleophilic substitution chemistry, as exemplified in Scheme 6.171. Here, the widely used reagent [18F]-/f-fluoroethyl tosylate was utilized to prepare several important 18F-labeled compounds [323],... 

The above benzaldehydes and bromides are useful for preparation of new radiopharmaceuticals and various amino acids in d, l (50 50) or enriched L form by asymmetric synthesis41. Two general reaction schemes have been proposed42 for the synthesis of [18F]-labelled compounds for routine medical uses starting from substituted [18F]-fluoroaromatic aldehydes 24 and [18F]fluorobenzyl chlorides and [18F]fluorobenzyl bromides 25. The latter have been applied for preparation of 18F-labelled neuroleptics 26 (equation 19)43. 

F-Labeled compounds are also available, via the ring-opening fluorination of cyclic sulfates, using tetramcthylammonium fluoride prepared from tetramethylammonium hydroxide and 18F-containing aqueous hydrogen fluoride.5 ... 

The formation of organic fluorides has been a difficult undertaking. However, an investigation of the effect of the solvent, leaving group, and source of the fluoride ion has shown that using tetrabutylammonium fluoride or CsF in r-amyl alcohol is able to convert arene sulfonates into fluorides rapidly at 90 °C in excellent yields (>80%).65 Since the half-life of 18F is only 110 min, this is an important advance as it allows one to label compounds with 18F for PET studies. 

These compounds have been synthesized31 in two steps (equation 11). In the first one nitroaldehydes 8-12 reacting with NCA K222 18F by aromatic nucleophilic substitution using either classical conditions (145 °C, 20 min, DMSO) or microwave heating (300 W, 2 min, DMSO) yield the corresponding 18F-labelled aromatic aldehydes 8a-12a in 50-75% yield. In the subsequent step the aromatic aldehydes are decar bony lated with tris(triph-enylphosphine)rhodium(I)chloride in 84 5% yields within 15 min at 150 °C in 1,4-dioxane, producing the desired title compounds 8b-12b. 

Both title compounds have been synthesized44 by halogen exchange reaction of Cs 18F with 2- and 6-bromonicotine (equation 21). NCA 18F-labelled 2-fluoronicotine has been obtained ready for injection in humans for study of the regional cerebral blood flow (rCBF) by PET and of the distribution of the nicotinic cholinergic receptors45,46. 

Various 18F-labelled N—F compounds have been obtained175 by reaction of [18F]F2 diluted to 1-2% in Ne with substrates shown in equations 81-86. The radioactive gas mixture has been bubbled through a solution of the substrate, or [18F]F2 produced by the 20Ne(d, a) 18F nuclear reaction has been condensed from the target gas into a Ni autoclave which contained the dry substrate. 

This potent [18F]-labelled muscarinic cholinergic receptor ligand 142182,183 has been synthesized184 by reductive amination of [2-18F]- and [4-18F]fluorobenzaldehyde with norben-zyldexetimide185a and sodium cyanoborohydride in a one-pot reaction (equation 92). Specific activities were 500-4000 mCi mmol-1 (142) (for the 2-fluoro compound) and 2400-8000 mCi mmol-1 (for the 4-fluoro compound). 

Fluorination of aryltrimethylsilanes with xenon difluoride is a method for the synthesis of 18F-labelcd compounds, since [18F]XeF2 can be prepared.28 1SF-Labeled aryl fluorides are also prepared by reaction of aryltrimethylsilanes with 18F-labcled acetyl hypofluorite and elemental fluorine.30 32... 

A large number of 18F-labeled organic molecules have now been synthesized, ranging from the simplest ([18F]fluoromethane) to quite large (radiolabeled proteins). A thorough review of compounds that have now been synthesized in fluorine-18 form is impossible. 

Labeling of biologically active molecules with fluorine-18 has taken great strides in the last two decades, largely due to the successful application of well-known reaction methods - nucleophilic and electrophilic fluorinations - to an increasingly diverse assortment of chemical structures. Two recent developments, the application of click chemistry and the use of protic solvents in nucleophilic fluorinations, deserve mention here as new directions in 18F-labeling that have the potential to significantly impact both the types of compounds labeled and the yields obtained. 

Synthesis of 18F-labelled N-fluoro compounds as electrophilic labelling reagents... 

For all the above methods and techniques one needs specially synthesised compounds which are suitably labelled 3H, 1251 and 14C for in vitro pharmacology, 123I for SPECT and 18F or nC for PET (table 1). 

A-Methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP, 92) injected in small amounts to man and other primates produce a clinical and neurochemical state similar to Parkinson s disease1"9,110. An analog of MPTP, 0-fluoromethyl-MPTP, 93, has been labelled with 18F1U by benzyl halide substitution on o-(chloromethyl)-MPTP hydrochloride or the corresponding brominated compound with [18F]fluoride in dry MeCN, to study the behaviour of MPTP in animal brains using PET. 

The title compound, l-[bis-(4-fluorophenyl)methyl]-4-(3-phenylpropenyl) piperazine, 123, clinically used as a calcium channel blocker of the piperazine class166, has been labelled with 18F by alkylation of Af-cinnamylpiperazine with 4-[18F]fluoro-4 -fluoroben-zhydryl chloride 124 (equation 73)167. The biodistribution of 123, its effect on the dopamine reuptake blockers and metabolic products are under investigation167. 

Continuing studies on 18F-fluoroalkylation of H-acidic compounds using the bifunctional fluoroalkanes 18F(CH2) X( = 1-3, X = Br, OMs, OTos) in the presence of the aminopolyether 2.2.2/potassium carbonate complex, Stocklin and coworkers171 obtained the best NCA labelling yields with tosylates. Fluoroethylation and fluoropropylation of phenol (equation 79) has been carried out with radiochemical yields of > 90%. In principle all Lewis bases are potential substrates for NCA fluoroalkylation. 

The title compounds, D-2 Dopamine agents, labelled with either 18F or 123I, have been prepared403. The corresponding precursors have been synthesized as shown in equations... 

The labeling of complex compounds can also be achieved by attaching small units, already containing the positron-emitting fluorine isotope, to the main molecular skeleton. Bifunctional fluoroalkanes 18F(CH2) X (n = 1-3, X =Br, OMs, OTs) could be prepared in > 90% radiochemical yield within 10 min. These compounds, especially the tosylates, were then reacted with phenols to give the corresponding [18F]fluoroethers390. Such a reaction... 

Both these 5-hydroxyindoles are natural compounds, playing an important role in the brain. 5-hydroxytryptophan (5-HTP) 315 is the metabolic precursor for the neurotransmitter serotonin melatonin 316 is a neurohormone involved in the regulation of chronobiological rhythms such as sleep and fertility306. They have been labelled with F-18, for in vivo metabolic imaging with PET, in reaction of dilute [18F]fluorine gas with melatonin or with 5-hydroxytryptophan in hydrogen fluoride307 at — 70 °C (equation 134). 

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