Biologically stable [18F]-labeled benzylfluoride derivatives1
Introduction
Low molecular weight radiopharmaceuticals labeled with positron emitting radionuclides such as 11C, 13N, and 18F, with half-lives of 20.3, 9.97, and 109.7 min, respectively, have been used together with positron emission tomography (PET) for imaging of brain, heart, and tumors 2, 6, 19. 18F-labeled tracers are often desired for receptor imaging because the longer half-life allows 18F-labeled tracers to be detected for a few hours after injection. [18F]-Fluorine can be introduced into an aromatic ring or aliphatic group of the target molecule at high specific activity using nucleophilic substitution.
Most of the radiopharmaceuticals injected are metabolized in the body and the metabolites are excreted in the bile or urine. If free radioactive halogen ion is released in the blood by dehalogenation reactions, they will accumulate in the thyroid or stomach for iodine and bone for fluorine 10, 20. Consequently, dehalogenation of radiohalogen labeled radiopharmaceuticals in vivo becomes a hindrance for imaging or leads to needless radiation exposure of patients. We have evaluated and reported on the usefulness of several compounds containing the [18F]-fluoro-benzyl group 8, 11, 12, but the structure and bone accumulation relationship has not been established.
Some defluorination reactions in vivo have been reported to take place by enzymatic reactions 1, 7. On the other hand, defluorination is easily induced with chemically unstable compounds. The 4-(4-nitro-benzyl)-pyridine (NBP) test 4, 5, a test of alkylating reactivity of an alkyl halogen, may be useful as an index of chemical stability. In this study, benzylchloride (BzCl) derivatives were selected as model compounds and the effect of substitution on alkylating reactivity were evaluated by the NBP test as guide for developing a stable 18F-labeled radiopharmaceutical containing benzylfluoride. Moreover, although it is generally said that released [18F]-fluoride ion after defluorination in vivo is accumulated in the bone as mentioned above, it remains unclear how 18F-labeled radiopharmaceuticals are defluorinated in vivo. On this basis, comparison of in vivo uptake in femur of rats and in vitro metabolism by rat hepatocytes was performed using currently available 18F-labeled compounds at our facility.
Section snippets
Materials and methods
All chemicals were purchased from Aldrich Chemical Company (Milwaukee, WI USA). The ultraviolet absorbance was measured with a Hewlett Packard 8452A Diode Array Spectrophotometer (Palo Alto, CA USA). Nuclear magnetic resonance (NMR) spectra were obtained on a Varian Gemini 2000 (200 MHz) (Palo Alto, CA USA) with tetramethylsilane as the internal standard. Mass spectra (MS) data were obtained on a Hewlett Packard GC-MS system with a 5890A series Gas Chromatograph and a 5989B series Mass
Synthesis of 18F-labeled compounds
(VII), the 18F labeling precursor of 4-[18F]-fluoromethylbenzoic acid methyl ester, was easily synthesized by esterification of 4-bromomethylbenzoic acid in methanol with anhydrous acid. (V), the precursor of 2-chloro-4-[18F]-fluoromethylbenzoic acid methyl ester, was synthesized from 3-chlorotoluene by the Friedel-Crafts reaction, oxidization of the acetyl group to carboxylic acid, bromination of the methyl group, and esterification of the carboxylic group.
Labeling of [18F]-FMeB(Me) and 4-[18
Discussion
We found that 3-chloro substitution on BzCl (3-Cl-BzCl) produced the weakest alkylating agent (Fig. 2). For electron withdrawing groups, the chloro substitution was less reactive at each position compared with the nitro substitution. The observed order of reactivity of both substituted derivatives was 2- > 4- > 3. For electron donating groups, the 4-methoxy BzCl showed the highest reactivity. It is likely that this high reactivity of 4-methoxy BzCl is due to the resonance effect that is
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2022, Advanced Drug Delivery ReviewsCitation Excerpt :That is perhaps, a minor problem to publishable optimized research, but it is also a more serious, perhaps lethal defect to any thoughts of a generally applicable clinically and commercially viable agent. From early and continuing work, it is now more fully appreciated that at the basic chemical level 18F- probably needs to be attached to an aromatic ring on or within the targeting agent [49], as aliphatic radiofluoride attachments have often led to pronounced in vivo defluorination and bone uptake although, as cited above, current active research is methodologically diverse. Certainly, other aspects of any prospective targeting agent including its own structure and function may also lead to unwanted bone deposition and these must be evaluated individually for each contemplated reagent, but the basic radiofluorine radiobiological chemistry discussed above is always a factor.
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Current address: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.