Designing Novel Contrast Agents for Magnetic Resonance Imaging. Synthesis and Relaxometric Characterization of three Gadolinium(III) Complexes Based on Functionalized Pyridine-Containing Macrocyclic Ligands
✍ Scribed by Silvio Aime; Eliana Gianolio; Davide Corpillo; Camilla Cavallotti; Giovanni Palmisano; Massimo Sisti; Giovanni B. Giovenzana; Roberto Pagliarin
- Publisher
- John Wiley and Sons
- Year
- 2003
- Tongue
- German
- Weight
- 188 KB
- Volume
- 86
- Category
- Article
- ISSN
- 0018-019X
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✦ Synopsis
The three novel pyridine-containing 12-membered macrocyclic ligands 1 ± 3 were synthesized. The coordinating arms are represented by three acetate moieties in 1 and 3 and by one acetate and two phosphonate moieties in 2. In all three ligands, the acetate arm in the distal position is substituted, with a benzyl group in 1 and 2 and with an arylmethyl moiety in 3. The relaxivities r 1p (20 MHz, 258) of Gd III complexes are: GD ¥ 1, r 1p 8.3 mm À1 s À1 ; GD ¥ 2, r 1p 8.1 mm À1 s À1 ; Gd ¥ 3, r 1p 10.5 mm À1 s À1 . 1 H-NMRD and 17 O-NMR T 2 data show that Gd ¥ 1 and Gd ¥ 3 contain two H 2 O molecules in the inner sphere, whereas the presence of two phosphonate arms allows the coordination of only one H 2 O molecule in Gd ¥ 2. Interestingly, the exchange lifetime of coordinated H 2 O in the three complexes is similar in spite of the difference in the coordination number of the Gd III ion (i.e., 9 in Gd ¥ 1 and Gd ¥ 3, and 8 in Gd ¥ 2). 1 H-Relaxometric measurements at different pH and in the presence of lactate and oxalate were carried out to get some insight into the formation of ternary complexes from Gd ¥ 1 and Gd ¥ 3. Finally, it was found that binding to human-serum albumin (HSA) of Gd ¥ 1 and Gd ¥ 2, though weak, yields limited relaxivity enhancements, likely as a consequence of effects on the hydration sphere caused by donor atoms on the surface of the protein.
Introduction. ± It is well established that the intrinsic contrast in magneticresonance images (MRI) can be augmented by the use of contrast agents, which are chemicals able to markedly enhance H 2 O protons relaxation rates [1] [2]. Most applications of contrast agents has dealt with the use of Gd III complexes because this metal ion couples a large magnetic moment with a long electronic-spin relaxation time. This metal does not possess any physiological function in mammals, and its administration as a free ion is extremely toxic even at low doses (10 ± 20 mmol/kg). For this reason, it is necessary to use ligands that form very stable chelates with Gd III ions [3] [4]. Scheme. Synthesis of Ligands 1 ± 3 i) MeOH, SOCl 2 , 08. ii) 1-Tosylaziridine, toluene, reflux. iii) TsCl, Py, 08. iv). t BuMe 2 SiCl, i Pr 2 EtN, MeCN, 08. v) 2,6-Bis(chloromethyl)pyridine, anh. K 2 CO 3 , MeCN, reflux. vi) 48% aq. HBr, PhOH, AcOH, reflux. vii) ClCH 2 COOH, KOH, H 2 O, 808. viii) 30% HBr in AcOH, 608. ix) H 3 PO 3 , (CH 2 O) n , 6m aq. HCl, reflux. x) BrCH 2 COOMe, Ag 2 CO 3 , MeCN, r.t. xi) KOH, MeOH, 608