One-step high-radiochemical-yield synthesis of [18F]FP-CIT using a protic solvent system

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Abstract

Although [18F] fluoropropylcarbomethoxyiodophenylnortropane (FP-CIT) is a promising radiopharmaceutical for dopamine transporter imaging, it has not been used for clinical studies because of low radiochemical yield. The purpose of our study was to develop a new radiochemistry method using a protic solvent system to obtain a high radiochemical yield of [18F]FP-CIT in single-step manual and automatic preparation procedures. [18F]F was trapped on a QMA Sep-Pak cartridge or PS-HCO3 cartridge and eluted with Cs2CO3/K222 buffer or TBAHCO3, respectively, or 8 μl of TBAOH was added directly to [18F]F/H218O solution in a reactor without using a cartridge. After drying, [18F] fluorination was performed with 2–6 mg of mesylate precursor, 100 μl of CH3CN and 500 μl of t-BuOH at 50–120°C for 5–30 min, followed by high-performance liquid chromatography (HPLC) purification to obtain the final product. For comparison, the same procedure was performed with a tosylate precursor. Manual synthesis gave a decay-corrected radiochemical yield of 52.2±4.5%, and optimal synthesis conditions were as follows: TBAOH addition, 4 mg of precursor, 100°C and 20 min of [18F] fluorination (n=3). We obtained low radiochemical yields of [18F]FP-CIT with carbonate elution systems such as Cs2CO3 or TBAHCO3. We also developed an automatic synthesis method based on manual synthesis results. In automatic production, we obtained a decay-corrected radiochemical yield of 35.8±5.2% after HPLC purification, and we did not have any synthesis failures (n=14). Here, we describe our new method for the synthesis of [18F]FP-CIT using a protic solvent system. This method gave a high radiochemical yield with high reproducibility and might enable [18F]FP-CIT to be used clinically and commercially.

Introduction

The pathological process of Parkinson's disease is accompanied by a loss of dopamine transporters (DAT) localized in presynaptic nigrostriatal nerve terminals. Therefore, in vivo imaging of DAT using radiopharmaceuticals has been very useful for the diagnosis and monitoring of Parkinson's disease. Cocaine analogs (e.g., β-CIT [1] and its derivatives such as CFT [2], PE2I [3], FE-CNT [4], IPT [5]) and fluoropropylcarbomethoxyiodophenylnortropane (FP-CIT) [6], [7], [8], [9], [10], [11], [12] have been shown to bind to DAT and have been studied as radiochemical ligands for DAT imaging in the human brain.

Among these, FP-CIT has high affinity to DAT, specific binding to DAT and fast kinetics, and has been labeled with [11C] carbon, [123I] iodine and [18F] fluoride [6], [7], [8], [9], [10], [11], [12]. However, due to the short half-life of [11C] carbon (t1/2=20 min), O-methyl-[11C]FP-CIT is not an ideal radiopharmaceutical for DAT positron emission tomography (PET) imaging since peak equilibrium in the striatum is attained over 70–90 min after the injection of FP-CIT. Recently, [123I]FP-CIT has been widely used for DAT imaging because it has been commercialized in Europe. However, it also has several limitations, including serotonin transporter uptake of radioactive metabolite and low resolution of single-photon emission computed tomography compared to PET.

[18F]FP-CIT has several advantages for DAT imaging, including fast kinetics, relatively long half-life of [18F] fluoride, a hydrophilic metabolite and high-resolution images with PET. Dosimetry results for humans showed low radiation exposure after injection of [18F]FP-CIT [13]. However, it has not been widely used for DAT imaging because of a very low radiochemical synthetic yield [9], [10].

There are two methods for the synthesis of [18F]FP-CIT. The first involves one-step synthesis from a mesylate nortropane precursor [9]. This reaction has the advantage of simple preparation but has shown a very low radiochemical yield (<5%) in previous reports. The second method is a two-step reaction in which [18F] fluorination of 1,3-propanediolditosylate is followed by alkylation with nor-β-CIT [10], [11]. This method also showed low radiochemical yield (∼5%) and required a long alkylation time at high temperature, which may cause epimerization to a less active α-isomer [14], [15].

Aliphatic nucleophilic substitution is generally performed in a polar aprotic solvent system such as CH3CN, and the use of a polar protic system such as alcohol has not previously been reported [16]. Recently, our group has developed a new chemistry for aliphatic nucleophilic substitution of tertiary alcohols. Using this polar protic solvent chemistry, we obtained a very dramatic increase in radiochemical yield for nucleophilic [18F] fluorination [17].

In this study, we developed a new method using a protic solvent system for the radiosynthesis of [18F]FP-CIT. We optimized this method with respect to phase-transfer catalyst, precursor amount and [18F] fluorination conditions in manual and fully automatic preparations to obtain high radiochemical yields of [18F]FP-CIT.

Section snippets

Chemicals and precursor

N-[3′-(mesyloxy)propyl]-2β-carbomethoxy-3β-(4′-iodophenyl)nortropane (mesylate precursor), N-[3′-(tosyloxy)propyl]-2β-carbomethoxy-3β-(4′-iodophenyl)nortropane (tosylate precursor) → N-[3′-(mesyloxy)propyl]-2β-carbomethoxy-3β-(4′-iodophenyl)nortropane (mesylate precursor; 1), N-[3′-(tosyloxy)propyl]-2β-carbomethoxy-3β-(4′-iodophenyl)nortropane (tosylate precursor; 2) and cold FP-CIT were supplied by FutureChem (Seoul, Korea). Other solvents and reagents, including t-BuOH with ACS reagent grade,

Results

We obtained a high radiochemical yield of [18F]FP-CIT with the TBAOH system only. In contrast, radiochemical yields with varying labeling conditions of Cs2CO3 or TBAHCO3 were <1% (data not shown).

The [18F] fluorination yield with the TBAOH system depended on precursor concentration, reaction temperature and incubation time. Fig. 3, Fig. 4 show the results of the radioTLC analysis of [18F] fluorination yield using TBAOH for manual synthesis under various reaction conditions. The crude radioTLC

Discussion

Manual and automated syntheses of [18F]FP-CIT were performed with high radiochemical yield and reproducibility. The obtained radiochemical yields were at least 10 times higher than those reported in previous studies [9], [10], using similar temperatures for [18F] fluorination and a smaller amount of the precursor. This dramatic increase in radiochemical yield is attributed to enhanced nucleophilic substitution catalyzed by a protic solvent system. Furthermore, our one-step preparation,

Conclusion

We describe a new synthesis method using a protic solvent system that dramatically increased the radiochemical yields of [18F]FP-CIT with high reproducibility. This new method could facilitate routine clinical application of [18F]FP-CIT.

Acknowledgments

This study was supported by a grant (2006-304) from the Asian Institute for Life Sciences (Seoul, Korea) and the Korean Ministry of Science and Technology, through its real-time molecular imaging research program.

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