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P.J. Riss, K. Stockhofe, F. Rösch Special Issue Review Received 16 May 2012, Revised 30 November 2012, Accepted 4 December 2012 Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jlcr.3018 Tropane-derived 11C-labelled and 18F-labelled DAT ligands† P. J. Riss,a* K. Stockhofe,b and F. Roeschb Radiolabelling of cocaine-derived 3-phenyltropanes for dopamine transporter positron emission tomography with 18F and 11C is reviewed. Keywords: fluorine-18; carbon-11; dopamine transporter; PET; 3-phenyltropane Introduction conditions for N-methylation of 3-phenyltropanes exist. These comprise the use of an excess of precursor without any base, Positron emission tomography (PET) studies of dopamine inorganic bases and trialkylamines in a dipolar aprotic solvent. transporter (DAT) availability provide valuable insights into the (À)-Cocaine has been labelled at two sites to obtain 1–5 presynaptic integrity of dopaminergic neurons in vivo. Several [O-methyl-11C]cocaine and [N-methyl-11C]cocaine.29–32 Cocaine is key challenges persist in the development of DAT ligands, these hydrolysed by butyryl choline esterase (E.C. 3.1.1.8) in blood to are DAT selectivity, due to close homology of the serotonin obtain ecgonine methyl ester and the free acid. Both metabolites transporter and the noradrenalin transporter, and slow equilibra- fail to enter the brain or penetrate the blood–brain barrier fi 0 tion of binding, caused by high binding af nity and adverse (BBB).33,34 Nevertheless, [11C]4 -fluorococaine (4) was brieflycon- metabolic degradation. A DAT ligand with ideal characteristics sidered as an alternative to [11C]cocaine in an attempt to overcome fi 6–14 11 has to be identi ed. Initial candidates included [ C]nomifen- hydrolytic cleavage of the ester function.32 The most problematic 18 11 sine, [ F]GBR13119, D-threo-[ C]methylphenidate and the alteration of cocaine is cytochrome-P450-mediated oxidative À 11 tropane (1)( )-N-[ C]cocaine (2). These suffered from low dealkylation of the nitrogen. The (À)-norcocaine formed by – striatum to cerebellum ratios (1.5 2.4), fast washout and low N-demethylation penetrates the BBB, binds to monoamine transpor- 5,6 selectivity. Despite the equipotent inhibition of DAT, serotonin ters and confounds reference tissue modelling.33,34 N-dealkylation transporter and noradrenalin transporter, 2 emerged as the lead represents a major shortcoming of the 3-phenyltropane lead.11–14 for DAT radiotracer development regardless of its short biologi- cal half-life and low selectivity. Substitution of the benzoate ester by an arene moiety to afford 3-phenyltropanes (3) resulted in a O-11C-Methylation of 3-phenyltropanes 40 times longer biological half-life.15,16 Radiolabelling via O-11C-methylation might offer distinct advan- Most cocaine-derived candidates share the distinctive absolute 11 configurations at carbons 1, 2, 3 and 5 of a mutual bicyclic tropane tages over N- C-methylation methods. The precursors are easily ((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane) scaffold (1)(Figure1). synthesised via ester hydrolysis under mild conditions, and the resultant carboxylic acids can be separated by a simple aqueous A variety of synthetic ligands has been developed, and a large 35 number of sophisticated modifications were introduced to tailor extraction. 11 b desired characteristics.17 Progress in 18F-labelled and 11C-labelled An C-labelled analogue of WIN 35,428 ( -CFT) 5, the gold radiotracers have been summarised occassionally.5,18–21 This standard for DAT studies in molecular biology and pharma- review focuses on radiolabelling of the 3-phenyltropane scaffold cology, was obtained by O-methylation of O-desmethyl- b 36,61,104 11 using 18Fand11C. -CFT. This early study used [ C]CH3I, and multiple 11C-Labelling aWolfson Brain Imaging Centre, University of Cambridge, Box 65 Addenbrooke’s Hospital, CB2 0QQ, Cambridge, UK 11 Substitution of a stable carbon atom with C provides an ele- bInstitute of Nuclear Chemistry, Johannes Gutenberg-University, Fritz-Strassmann- gant way of radiotracer development, although incorporation Weg2,55128,Mainz,Germany of the radiolabel into a substrate should ideally be achieved in a single synthetic transformation.22 Considerable effort has been *Correspondence to: P. J. Riss, Wolfson Brain Imaging Centre, University of 11 11 Cambridge, Box 65 Addenbrooke’s Hospital, CB2 0QQ, Cambridge, UK. spent on the development of C-synthons starting from [ C] E-mail: [email protected] CH and [11C]CO .23–25 To date, most 11C-radiotracers are 4 2 † obtained by alkylation of heteroatom nucleophiles using [11C] This article is published in Journal of Labelled Compounds and Radiopharma- 11 26–28 ceuticals as a special issue on Carbon-11 and fluorine-18 chemistry devoted to CH3Ior[ C]CH3OTf (Schemes 1 and 2). molecular probes for imaging the brain with PET, edited by Frédéric DOLLÉ, Although precautions have to be taken to suppress side reac- Service Hospitalier Frédéric Joliot Institut d’Imagerie BioMédicale - CEA 4 Place tions and improve trapping of the synthon, a wide range of viable du Général Leclerc - F-91406 Orsay - France. 149 J. Label Compd. Radiopharm 2013, 56 149–158 Copyright © 2013 John Wiley & Sons, Ltd. P. J. Riss et al. Biography e.g. 86Yand94mTc. In 1992 he was appointed professor of nuclear chemistry at the Institute of Nuclear Chemistry at the Patrick Riss was born in Aachen, Johannes Gutenberg-University Mainz, Germany. He is carrying Federal Republic of Germany, in out developments on fundamental and applied radiochemistry 1979. He studied Chemical Engi- and radiopharmaceutical chemistry with a focus on radiometals neering and Nuclear Chemistry in and radionuclide generators. Here, the pathway to carrier-free Jülich and Mainz before obtaining 177Lu was developed. New approaches towards the design ’ ‘ adoctorate summa cum laude in and use of generators such as 68Ge/Ga, 44Ti/Sc, 140Nd/Pr etc. natural sciences in 2008. Through- have been elaborated. He is involved in teaching, training out his time in Mainz he was and education and is one of the editors of the “Handbook of engaged in the development of Nuclear Chemistry”. 11C, 18Fand68Ga labelled 3-phe- nyltropanes for dopamine trans- porter imaging with PET. He spent 8 O O 9 N N O N O time working overseas at the 1 2 7 Medical Department, Brookhaven O R National Laboratory, Upton, NY in 5 4 6 3 O 2008 and at the National Institute of Mental Health, National Institutes of Health, Bethesda, MD in 2011. In his current position 12 3 as a Senior Research Associate at the University of Cambridge, UK, Figure 1. Tropane (1), (À)-cocaine (2) and 3-phenyltropane (3). he is affiliated with the Wolfson Brain Imaging Centre and the Behavioural and Clinical Neuroscience Institute. His research O 11 interests include biocatalysis, development of radiolabelling 1. base, solvent O CH3 R N OH 11 11 R N methodology, discovery and validation of PET radiotracers and 2. CH3Ior CH3OTf O application of PET imaging in animal models of human disease. Biography R' R' 11 Katharina Stockhofe was born in Scheme 1. O- C-methylation of 3-phenyltropanes. Duisburg, Germany in 1986. She graduated from the Landfermann- O 1. base, solvent O HN O 11 11 H 11C N Gymnasium with Abitur in 2006 and 2. CH3Ior CH3OTf 3 O started to study Biomedical Chemis- try at the Johannes Gutenberg- University Mainz. In 2012 she R' R' obtained her Diploma in radiophar- Scheme 2. N-11C-methylation of phenyltropanes. maceutical and bioinorganic chem- istry. For her diploma thesis in the group of Prof. Tobias Ross and examples of similar conditions were to follow for a variety of – Prof. Frank Rösch at the Institute 3-phenyltropanes, for example, b-CMT 6 and b-CCT 7 (Table 1).38 40 of Nuclear Chemistry in Mainz Purification of the 11C-labelled products is achieved by semi- she investigated new DAT-Ligands preparative HPLC providing the radiotracers in high specific 68 for Ga-labelling. In her work she activity and radiochemical purity. The N-(3-fluoroprop-1-yl) analo- synthesized phenyltropanes as model structures for such labeling gue of 8,FP-b-CIT 9, was evaluated because of a faster washout studies. In 2012 she started her PhD in the group of Prof. Ross and rate and higher target to non-target ratio, as established in a Prof. Rösch and continued the research on metal-based brain 123 ligands. In another project she is developing different nanodi- preliminary I-SPECT (Single Photon Emission Tomography) study.41,42 A similar observation was made with [123I]altropaneW 10, mensional structures, nanomaterials and makromolekules for 11 labeling with chelator needing metals like 68Ga and with 18F. and its much more rapid kinetic profile warranted C-labelling and evaluation.43 PE2I 11, a close analogue of 10, was developed, 11 123 44–46 Biography and C-labelling as well as I-labelling was investigated. 11 PR04.MZ 12 was synthesised using [ C]CH3I and the carboxylic Frank Rösch wasborninChem- acid precursor TFA salt in combination with rubidium carbonate nitz, Germany, in 1955. He studied as base, to result in quantitative incorporation of 11C.47 nuclear and radiochemistry at the Considerable effort has been spent to optimise the labelling Technical University Dresden grad- protocols for 3-phenyltropanes. In particular, substitution of uated in 1981 and obtained a PhD 11 11 in 1984. Subsequently, he spent a [ C]CH3I with [ C]CH3OTf facilitated synthesis of 8 under more fellowship at the Laboratory for mild conditions. A minor modification was also employed in the 11 Nuclear Problems, Joint Institute C-methylation of FE-b-CIT 13, and few precursors were required for Nuclear Research, Dubna, Sowjet in a shorter reaction time.46,48 Remarkably improved 11C-methylation Union, investigating physico- yields were also reported for 11 by several groups.
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