N N N CO 2 H HO 2 C HO 2 C CO 2 H CO 2 H N N HO 2 C HO 2 C HO 2 C N HO 2 C HO 2 C N N HO 2 C HO 2 C HO 2 C N HO 2 C HO 2 C DTPA Cy-DTPA Ph-DTPA 1 TETRAHEDRON LETTERS Tetrahedron Letters 43 (2002) 3003–3005 Pergamon Synthesis of a new chelating agent derived from phenylenediamine for application in radioimmunotherapy Se ´bastien G. Gouin, a,b Jean-Franc ¸ois Gestin, b,c Alain Reliquet, a Jean Claude Meslin a and David Deniaud a, * a Laboratoire de Synthe `se Organique, UMR CNRS 6513, Faculte ´ des Sciences et des Techniques, 2 rue de la Houssinie `re, BP 92208, 44072 Nantes Cedex, France b INSERM U463, Chimie des bioconjugue ´s, 9 quai Moncousu, 44093 Nantes Cedex, France c CHELATEC SAS, Institut de Biologie, 9 quai Moncousu, 44093 Nantes Cedex, France Received 4 February 2002; accepted 27 February 2002 Abstract—We report the synthesis of a new diethylenetriaminepentaacetic acid (DTPA) analogue, Ph-DTPA, possessing an aromatic rigid skeleton. This precursor of a bifunctional chelating agent was synthesized by elaboration of the intermediate N-(o -aminophenyl)ethylenediamine and obtained in five steps with an overall yield of 42%. Preliminary complexation studies between Ph-DTPA and 153 Sm has been carried out. © 2002 Elsevier Science Ltd. All rights reserved. For many years, complexes combining metals with DTPA and its derivatives have been widely used in magnetic resonance imaging (MRI), 1–5 radiotherapy 6–8 and radiodiagnosis. 9 In particular, the gadolinium– (DTPA) complex is currently used in clinical applica- tions as a contrast agent in MRI. 10,11 Moreover, many complexes combining lanthanides with DTPA ana- logues have proved stable enough for use in a physio- logical medium as radiopharmaceuticals. 12,13 Since the introduction of this family of chelating agents, develop- ments have been directed essentially at increasing the stability of the resulting complexes. 14,15 The most promising results have been based on studies to improve the rigidity of the chelating structure. The introduction of a semi-rigid preformed skeleton, which minimizes the freedom of donor atoms, has had a significant effect on the stability of the metal complexes formed. 16 Notably, the teams of R. D. Hancock and then M. W. Brechbiel have shown that DTPA ana- logues with a semi-rigid structure of cyclohexyl (Cy- DTPA), 17,18 piperidinyl (PIP-DTPA) or azaparyl (AZEP-DTPA) 19 type prove considerably more stable in vivo. On this basis, our recent research has been directed at developing stereoisomer chelating agents based on ethylenediaminetetraacetic acid analogues with a cyclopentanic skeleton. 20 The synthesis of the DTPA analogue phenyleneethylenetriamine pentaacetic acid (Ph-DTPA) reported here provides a chelating agent even more rigid than Cy-DTPA and with an aromatic skeleton (Scheme 1). Scheme 1. * Corresponding author. Tel.: +33-2-51-12-54-57; fax: +33-2-51-12-54-02; e-mail: david.deniaud@chimie.univ-nantes.fr 0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII:S0040-4039(02)00410-0