PET (positron emission tomography) is a powerful diagnostic and imaging technique which requires short-lived positron emitting isotopes. The most commonly used are accelerator-produced (11)C and (18)F. An alternative is the use of metallic positron emitters. Among them (68)Ga deserves special attention because of its availability from long-lived (68)Ge/(68)Ga generator systems which render (68)Ga radiopharmacy independent of an onsite cyclotron. The coordination chemistry of Ga(3+) is dominated by its hard acid character. A variety of mono- and bifunctional chelators have been developed which allow the formation of stable (68)Ga(3+)complexes and convenient coupling to biomolecules. (68)Ga coupling to small biomolecules is potentially an alternative to (18)F- and (11)C-based radiopharmacy. In particular, peptides targeting G-protein coupled receptors overexpressed on human tumour cells have shown preclinically and clinically high and specific tumour uptake. Kit-formulated precursors along with the generator may be provided, similar to the (99)Mo/(99m)Tc-based radiopharmacy, still the mainstay of nuclear medicine.

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Somatostatin-based radioligands have been shown to have sensitive imaging properties for neuroendocrine tumours and their metastases. The potential of [(55)Co(dotatoc)] (dotatoc =4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-ylacetyl-D-Phe-(Cys-Tyr-D-Trp-Lys-Thr-Cys)-threoninol (disulfide bond)) as a new radiopharmaceutical agent for PET has been evaluated. (57)Co was used as a surrogate of the positron emitter (55)Co and the pharmacokinetics of [(57)Co(dotatoc)] were investigated by using two nude mouse models. The somatostatin receptor subtype (sst1-sst5) affinity profile of [(nat)Co(dotatoc)] on membranes transfected with human somatostatin receptor subtypes was assessed by using autoradiographic methods. These studies revealed that [(57)Co(dotatoc)] is an sst2-specific radiopeptide which presents the highest affinity ever found for the sst2 receptor subtype. The rate of internalisation into the AR4-2J cell line also was the highest found for any somatostatin-based radiopeptide. Biodistribution studies, performed in nude mice bearing an AR4-2J tumour or a transfected HEK-sst2 cell-based tumour, showed high and specific uptake in the tumour and in other sst-receptor-expressing tissues, which reflects the high receptor binding affinity and the high rate of internalisation. The pharmacologic differences between [(57)Co(dotatoc)] and [(67)Ga(dotatoc)] are discussed in terms of the structural parameters found for the chelate models [Co(II)(dota)](2-) and [Ga(III)(dota)](-) whose X-ray structures have been determined. Both chelates show six-fold coordination in pseudo-octahedral arrangements.

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We report the synthesis and characterization of the novel ligand H5EPTPA‐C16 ((hydroxymethylhexadecanoyl ester)ethylenepropylenetriaminepentaacetic acid). This ligand was designed to chelate the GdIII ion in a kinetically and thermodynamically stable way while ensuring an increased water exchange rate (kex) on the GdIII complex owing to steric compression around the water‐binding site. The attachment of a palmitic ester unit to the pendant hydroxymethyl group on the ethylenediamine bridge yields an amphiphilic conjugate that forms micelles with a long tumbling time (τR) in aqueous solution. The critical micelle concentration (cmc = 0.34 mM) of the amphiphilic [Gd(eptpa‐C16)(H2O)]2− chelate was determined by variable‐concentration proton relaxivity measurements. A global analysis of the data obtained in variable‐temperature and multiple‐field 17O NMR and 1H NMRD measurements allowed for the determination of parameters governing relaxivity for [Gd(eptpa‐C16)(H2O)]2−; this is the first time that paramagnetic micelles with optimized water exchange have been investigated. The water exchange rate was found to be ${k{{\,298\hfill \atop {\rm ex}\hfill}}}$ = 1.7×108 s−1, very similar to that previously reported for the nitrobenzyl derivative [Gd(eptpa‐bz‐NO2)(H2O)]2− (${k{{\,298\hfill \atop {\rm ex}\hfill}}}$ = 1.5×108 s−1). The rotational dynamics of the micelles were analysed by using the Lipari–Szabo approach. The micelles formed in aqueous solution show considerable flexibility, with a local rotational correlation time of ${\tau {{\,298\hfill \atop {\rm l0}\hfill}}}$ = 330 ps for the GdIII segments, which is much shorter than the global rotational correlation time of the supramolecular aggregates, ${\tau {{298\hfill \atop {\rm g0}\hfill}}}$ = 2100 ps. This internal flexibility of the micelles is responsible for the limited increase of the proton relaxivity observed on micelle formation (r1 = 22.59 mM−1 s−1 for the micelles versus 9.11 mM−1 s−1 for the monomer chelate (20 MHz; 25 °C)).

The in vitro relaxivity of the Gd III -glycoconjugates was studied by 1 H nuclear magnetic relaxation dispersion (NMRD), yielding parameters close to those reported for other DOTA monoamides.The known recognition of sugars by lectins makes these glycoconjugates good candidates for medical imaging agents (MRI and gamma scintigraphy).3

The macrocyclic ligand DO2A (1,4,7,10-tetraazacyclododecane-1,7-bis(acetic acid)) was prepared and used as a building block for four new macrocyclic ligands having mixed side-chain chelating groups. These ligands and their complexes with Mg(II), Ca(II), and Ln(III) were studied extensively by potentiometry, high-resolution NMR, and water proton relaxivity measurements. The protonation constants of all compounds compared well with those of other cyclen-based macrocyclic ligands. All Ca(II) complexes were found to be more stable than the corresponding Mg(II) complexes. Trends for the stabilities of the Ln(III) complexes are discussed and compared with literature data, incorporating the effects of water coordination numbers, Ln(III) contraction, and the nature of the side chains and the steric hindrance between them. (1)H NMR titrations of DO2A revealed that the first and second protonations take place preferentially at the secondary ring nitrogens, while the third and fourth involved protonation of the acetates. (17)O NMR shifts showed that the DyDO2A(+) complex had two inner-sphere water molecules. Water proton spin-lattice relaxation rates for the GdDO2A(+) complex were also consistent with water exchange between bulk water and two inner-sphere Gd(III) coordination positions. Upon formation of the diamagnetic complexes of DO2A (Ca(II), Mg(II), La(III), and Lu(III)), all of the macrocyclic ring protons became nonequivalent due to slow conformational rearrangements, while the signals for the acetate CH(2) protons remained a singlet.

In spite of the fact that Group 13 metal ions (Al(3+), Ga(3+), In(3+) and Tl(+/3+)) show no main biological role, they are NMR-active nuclides which can be used in magnetic resonance spectroscopy of biologically relevant systems. The fact that these metal ions are quadrupolar (with the exception of thallium) means that they are particularly sensitive to ligand type and coordination geometry. The line width of the NMR signals of their complexes shows a strong dependence on the symmetry of coordination, which constitutes an effective tool in the elucidation of structures. Here we report published NMR studies of this family of elements, applied to systems of biological importance. Special emphasis is given to binding studies of these cations to biological molecules, such as proteins, and to chelating agents of radiopharmaceutical interest. The possibility of in vivo NMR studies is also stressed, with extension to (27)Al-based MRI (magnetic resonance imaging) experiments.