This study evaluated the in vitro and in vivo characteristics of a new dopamine transporter (DAT) radioligand, [(18)F]fluoroethyl(FE)PE2I, by autoradiography from postmortem human brain and by positron emission tomography (PET) in three cynomolgus monkeys. In the autoradiography experiments, high [18F]FE-PE2I accumulation was observed in caudate and putamen that was selectively abolished by GBR12909 or beta-CIT but not by maprotiline. High doses of citalopram (>5 microM) also inhibited [18F]FE-PE2I binding in the striatum. In vitro Ki of the radioligand was 12 nM at rodent dopamine transporter. [18F]FE-PE2I brain uptake measured by PET was approximately 4-5% of the injected dose, with highest uptake in striatum followed by midbrain and thalamus, lower uptake in neocortex, and lowest in cerebellum. Peak specific binding in striatum was reached approximately 40 min and in midbrain 20-30 min postinjection. The ratio-to-cerebellum was 7-10 in striatum and 1.5-2.3 in midbrain. BP(ND) measured with simplified reference tissue method using the cerebellum as reference region was 4.5 in striatum and 0.6 in midbrain. No displacement was shown after citalopram or maprotiline administration, while GBR12909 decreased the binding in striatum and midbrain to the level of cerebellum. [18F]FE-PE2I showed relatively fast elimination and metabolism with the presence of two metabolite peaks with similar retention time as the labeled metabolites of [11C]PE2I. [18F]FE-PE2I showed in vivo selectivity for the DAT and compared with [11C]PE2I, it showed faster kinetics and earlier peak equilibrium. The potential influence of the two radiometabolites on PET quantification requires further evaluation.

nortropane ( 18 F-FE-PE2I) is a novel radioligand for dopamine transporter (DAT) PET. As compared with 11 C-N-(3-iodoprop-2E-enyl)-2b-carbomethoxy-3b-(4-methylphenyl)nortropane ( 11 C-PE2I), 18 F-FE-PE2I shows faster kinetics and more favorable metabolism, with less production of a radiometabolite with intermediate lipophilicity (M1), which-in the case of 11 C-PE2I-has been shown to enter the rat brain. In this study, we compared DAT quantification with 11 C-PE2I and 18 F-FE-PE2I in nonhuman primates, using kinetic and graphical analysis with the input function of both the parent and the radiometabolite, to assess the potential contribution of the radiometabolite. Methods: Three rhesus monkeys were examined with 11 C-PE2I and 18 F-FE-PE2I using the HRRT system. Arterial input functions of the parent and radiometabolite M1 were measured. Kinetic and graphical analyses were applied using either the parent input (methods 1 and 3) or the parent plus radiometabolite input (methods 2 and 4). Outcome measures were distribution volumes (V T and V ND ), specific-to-nondisplaceable tissue radioactivity ratio at equilibrium (BP ND ; parent input), and specific-to-nondisplaceable tissue radioactivity ratio at equilibrium in the presence of metabolites (R T ; parent plus radiometabolite input). Results: 11 C-PE2I showed higher distribution volumes than 18 F-FE-PE2I calculated with methods 1 and 3 (striatal V T , ;300%; V ND in cerebellum, ;30%). With methods 2 and 4, V T in the striatum was approximately 60% higher in the case of 11 C-PE2I, whereas no difference in V ND was found in the cerebellum. For each radioligand, BP ND estimated with methods 1 and 3 tended to be higher than R T estimated with methods 2 and 4. However, the bias of BP ND , compared with R T , was much larger for 11 C-PE2I (40%-60% in the caudate and putamen) than for 18 F-FE-PE2I (,10% in the caudate and putamen). Conclusion: The direct comparison between the radioligands confirmed that 18 F-FE-PE2I shows faster kinetics and more favorable metabolism than 11 C-PE2I. The kinetic and graphical analyses with the input function of the parent and radiometabolite showed that the bias in BP ND was much lower for 18 F-FE-PE2I than for 11 C-PE2I and suggested that the lower production of the radiometabolite M1 would make 18 F-FE-PE2I more suitable for the DAT quantification. Further studies in humans are necessary to confirm these findings.

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Abstract(R)‐(−)‐2‐[11C]Methoxy‐N‐n‐propylnorapomorphine ([11C]MNPA ([11C]2)) is an agonist radioligand of interest for imaging D2/D3 receptors in vivo. Here we sought to develop an improved radiosynthesis of this radioligand. Reference 2 was synthesized in nine steps with an overall yield of about 5%, starting from codeine. Trimethylsilyldiazomethane proved to be a practical improvement in comparison to diazomethane in the penultimate methylation step. A protected precursor for radiolabeling ((R)‐(−)‐2‐hydroxy‐10,11‐acetonide‐N‐n‐propylnoraporphine, 4) was prepared from (R)‐(−)‐2‐hydroxy‐N‐n‐propylnorapomorphine (1) in 30% yield. [11C]2 was prepared from 4 via a two‐step one‐pot radiosynthesis. The first step, methylation of 4 with [11C]methyl triflate, occurred in quantitative radiochemical yield. The second step, deprotection of the catechol moiety with HCl and heat, yielded 60–90% of [11C]2 giving an overall incorporation yield from [11C]methyl triflate of 60–90%. In a typical run more than 1 GBq of [11C]2, was produced from carbon‐11 generated from a 10‐min proton irradiation (16 MeV; 35 µA) of nitrogen–hydrogen target gas. The radiochemical purity of [11C]2 was > 99% and specific radioactivity at the time of injection was 901±342 GBq/µmol (n=10). The total synthesis time was 35–38 min from the end of radionuclide production. The identity of [11C]2 was confirmed by comparing its LC‐MS/MS spectrum with those of reference 2 and (R)‐(−)‐10‐methoxy‐2,11‐dihydroxy‐N‐n‐propylnoraporphine. Copyright © 2009 John Wiley & Sons, Ltd.