Revival of TE2A; a better chelate for Cu(II) ions than TETA?w Darpan N. Pandya, a Jung Young Kim, b Jeong Chan Park, a Hochun Lee, c Prasad B. Phapale, d Wonjung Kwak, a Tae Hyun Choi, b Gi Jeong Cheon, b Young-Ran Yoon d and Jeongsoo Yoo* a Received (in Cambridge, UK) 8th December 2009, Accepted 25th February 2010 First published as an Advance Article on the web 23rd March 2010 DOI: 10.1039/b925703a A highly effective synthetic route for TE2A was developed and the 64 Cu-labeled TE2A complexes showed higher kinetic inertness and faster clearance than most commonly used TETA analogs. Interest in the synthesis, structures and properties of metal complexes based on various types of N-functionalized polyazamacrocycles has increased tremendously over the last few decades, due to their potential application in the field of medical imaging and therapy (e.g. MRI contrast agents, diagnostic radiopharmaceuticals and radioimmunotherapy). 1–3 In particular, cyclen and cyclam backbones containing N-acetic acid pendant arms e.g. DOTA, 4 DO2A, 5 TETA, 6 cross-bridged-DO2A (CB-DO2A), 7 cross-bridged-TE2A (CB-TE2A) 6,8 and their derivatives have been intensively studied as potential bifunctional chelates (BFCs) for imaging and therapy (Fig. 1). The metal complexes of these BFC agents are found to show different levels of kinetic inertness and thermodynamic stability when used in vivo, depending on their ligand structure. 9–12 The overall charge of the metal complexes, which is determined mostly by the number of coordinated acetate pendent arms and the oxidation state of the metal ions, also has a huge effect on the clearance pattern of the complexes and activity uptake in non-target organs. 13 The relationship between their structure and in vivo physical/ biological properties is fairly well documented in the case of cyclen-based BFCs. However, very few studies have been carried out on some of their cyclam-based counterparts, in spite of the structural similarity between cyclen and cyclam. To our surprise, we found that although TE2A was first synthesized in 1988, 14 only a few metal complexes of TE2A were further reported by the same group in the early 1990s. 15 No systematic studies on the use of TE2A as a potential BFC have been carried out so far. When considering that the 64 Cu–DO2A complex shows faster clearance than its DOTA counterpart 11 and that the TE2A derivative, CB-TE2A, forms extremely stable Cu(II) complexes, 7 this oversight becomes all the more mysterious. To the best of our knowledge, there is only one report on the synthesis of TE2A in the literature, which was published by Parker et al. 14,16 This synthetic procedure suffers from several serious disadvantages, such as the co-formation of various regioisomers (cis and two different trans) with other substituted by-products of the cyclam, tedious column purification, harsh reaction conditions and, therefore, a very low overall yield from the cyclam (16%). Even though twenty years have passed since the first report of TE2A, the regioselective synthesis of 1,8-N,N 0 -difunctionalized cyclams (e.g. TE2A) over the unwanted formation of other regioisomers and other substituted products is still a great challenge for the synthetic chemist. Herein we report a new facile synthetic protocol for TE2A and demonstrates its usefulness as an effective chelate for 64 Cu. First, we protected the cyclam using formaldehyde to give the tricyclic bis-aminal 2 containing two six-membered rings. The alkylation of compound 2 with t-butyl bromoacetate afforded the selective dialkylation at the 1,8-position without the formation of any cis-disubstituted product. The product 3 having two non-adjacent quaternary nitrogen atoms is insoluble in CH 3 CN and was isolated by simple filtration (see Scheme 1). The cleavage of the two aminal bridges and ester hydrolysis of 3 could be achieved in one step by treating it with 5 equivalent of KOH in an ethanol–water mixture (1 : 1) at 80 1C for 8 h, and the crude product was then run through Dowex ion-exchange resin (1X8, OH form) to afford the hydrochloride salt of TE2A in excellent yield. This new synthetic method for TE2A is very straightforward and very easy to handle. No tedious column purification is needed and the overall yield attained from the cyclam is 86%, which is much higher than the value of 16% achieved in the previously reported syntheses. 16 TE2A (4) and the intermediate (3) were fully characterized by NMR spectroscopy, elemental analysis and HR-MS. Fig. 1 Some commonly used bifunctional chelators. a Department of Molecular Medicine and Nuclear Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea. E-mail: yooj@knu.ac.kr; Fax: +82-53-426-4944; Tel: +82-53-420-4947 b Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea c Department of Applied Chemistry, Kumoh National Institute of Technology, Yangho-dong 1, Gumi, Kyeongbuk 730-701, Republic of Korea d Department of Molecular Medicine, Kyungpook National University School of Medicine & Clinical Trial Center, Kyungpook National University Hospital, Daegu 700-422, Republic of Korea w Electronic supplementary information (ESI) available: Experimental procedures for the synthesis, acidic decomplexation, cyclic voltammetry, radiolabeling and biodistribution studies of TE2A. Half-lives for acid decomplexation and reduction potentials of Cu–DOTA and Cu–CB-TE2A. See DOI: 10.1039/b925703a This journal is  c The Royal Society of Chemistry 2010 Chem. Commun., 2010, 46, 3517–3519 | 3517 COMMUNICATION www.rsc.org/chemcomm | ChemComm Downloaded by Seoul National University on 29 October 2012 Published on 23 March 2010 on http://pubs.rsc.org | doi:10.1039/B925703A View Online / Journal Homepage / Table of Contents for this issue