Vasovist^® is the tradename of a Gd(III) complex which was the first intravascular contrast agent (see Box 4.3) approved in the EU for use in magnetic resonance angiography. Interactions between the lipophilic domain of the contrast agent and human serum albumin allow Vasovist^® to bind reversibly to the protein. Vasovist^® has the formula Na₃[GdL(OH₂)] where the ligand Lⁿ⁻ is derived from H_nL shown in Fig. 27.12. 

(a) What is the value of n in Lⁿ⁻ and H_nL? 

(b) Explain why one part of the ligand is described as being lipophilic.

(c) In Na₃[GdL(OH₂)], the Gd³⁺ ion is 9-coordinate. Suggest a possible coordination environment for the metal ion, and indicate how Lⁿ⁻ is likely to coordinate to Gd³⁺. 

(d) Why is H_nL chiral? 

(e) Starting from (R)-H_nL, four diastereoisomers of [GdL(OH₂)]³⁻ are possible: ΔR, R, ΔR,S, ∧R,R, ∧R,S. How do these arise? 

(f) The FAB mass spectrum of Na₃[GdL(OH₂)] shows peak envelopes at m/z 981, 959, 937 and 915. Suggest assignments for these peaks.

Box 4.3.

Figure 27.12.

Transcribed Image Text:

BIOLOGY AND MEDICINE Box 4.3 Magnetic resonance imaging (MRI) Magnetic resonance imaging (MRI) is a rapidly expanding clin- ical technique to obtain an image of, for example, a human organ or tumour. In 2003, approximately 10 000 MRI units performed 75 million scans worldwide and since then these numbers have risen dramatically. The impact of this non-invasive technique on clinical medicine was recognized by the award of the 2003 Nobel Prize in Medicine to Paul Lauterbur and Peter Mansfield. The MRI image is generated from information obtained from the ¹H NMR spectroscopic signals of water. The signal intensity depends upon the proton relaxation times and the concentration of water. The relaxation times can be altered, and the image enhanced, by using MRI contrast agents. Coordination com- plexes containing paramagnetic Gd³+, Fe³+ or Mn²+ are poten- tially suitable as contrast agents and, of these, complexes containing the Gd³+ ion have so far proved to be especially useful. As a free ion, Gd³+ is extremely toxic and, therefore, to minimize side-effects in patients, Gd³+ must be introduced in the form of a complex that will not dissociate in the body. Chelating ligands are particularly suitable (see Chapter 7 for a discussion of stability constants). Ligands such as [DTPA- (the conjugate base of H,DTPA, drawn below) possess both O- and N-donor atoms, and form gadolinium(III) complexes in which the Gd³+ ion exhibits a high coordination number (see Chapter 19). For example, in [Gd(DTPA)(OH₂)], the Gd³+ centre is 9-coordinate. The complex [Gd(DTPA) (OH₂)]² was approved in 1988 for medical use as an MRI con- trast agent and is used under the brand name of Magnevist. Two other approved contrast agents are [Gd(DTPA-BMA)(OH₂)] (trade name Omniscan) and [Gd(HP-DO3A)(OH₂)] (ProHance). The solid state structure of [Gd(DTPA-BMA)(OH₂)] is shown below, and confirms a 9-coordinate metal centre. Magne- vist, Omniscan and ProHance are classed as extra-cellular con- trast agents, meaning that, once injected into a patient, they are distributed non-specifically throughout the plasma and