Alan M. Sargeson

Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64Cu-SarAr immunoconjugates

The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement 18F-FDG. Copper-64 (64Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability of conventional chelates has limited its clinical application. The objective of this work was to evaluate the novel chelating agent SarAr (1-N-(4-aminobenzyl)-3, 6,10,13,16,19-hexaazabicyclo[6.6.6] eicosane-1,8-diamine) for use in developing a new class of tumor-specific 64Cu radiopharmaceuticals for imaging neuroblastoma and melanoma. The anti-GD2 monoclonal antibody (mAb) 14.G2a, and its chimeric derivative, ch14.18, target disialogangliosides that are overexpressed on neuroblastoma and melanoma. Both mAbs were conjugated to SarAr using carbodiimide coupling. Radiolabeling with 64Cu resulted in >95% of the 64Cu being chelated by the immunoconjugate. Specific activities of at least 10 μCi/μg (1 Ci = 37 GBq) were routinely achieved, and no additional purification was required after 64Cu labeling. Solid-phase radioimmunoassays and intact cell-binding assays confirmed retention of bioactivity. Biodistribution studies in athymic nude mice bearing s.c. neuroblastoma (IMR-6, NMB-7) and melanoma (M21) xenografts showed that 15–20% of the injected dose per gram accumulated in the tumor at 24 hours after injection, and only 5–10% of the injected dose accumulated in the liver, a lower value than typically seen with other chelators. Uptake by a GD2-negative tumor xenograft was significantly lower (<5% injected dose per gram). MicroPET imaging confirmed significant uptake of the tracer in GD-2-positive tumors, with minimal uptake in GD-2-negative tumors and nontarget tissues such as liver. The 64Cu-SarAr-mAb system described here is potentially applicable to 64Cu-PET imaging with a broad range of antibody or peptide-based imaging agents.

Developments in the synthesis and reactivity of encapsulated metal ions

The use of the template strategy to make larger and smaller cavity sizes of encapsulating ligands is explored and the effect of cavity size and stereochemistry on redox potentials and electron transfer reactions is examined. The cages have also been modified in a variety of ways by oxidation of the ligand to hydroxylamines, imines, amides and aromatic systems. The mechanisms of extrusion of metal ions from the cages are also discussed. Much of the interesting chemistry associated with the hexaamine metal ion cages has been related to the rapid redox changes they undergo and their unusual stability, both in a kinetic and thermodynamic sense. These factors make them useful as redox reagents of an innocent kind and the Stability allows experiments which mostly are not feasible with their tris(bidentate) analogues. The elaboration of the cages has been carried on with respect to these properties but there are basic issues still to be answered. For example, what happens if the cavity size is increased; is the complex destabilized? Are the redox rates altered dramatically? Is the coordinated ligand reactive and how does the metal ion influence that issue? How does the metal ion come out of the cage? These are all questions which need to be answered in order to understand and use the encapsulation chemistry effectively and this lecture addresses some of those matters. One obvious problem has been to increase the natural cavity size in the ligand in order to accommodate larger low oxidation state ions and also modulate the redox potentials of couples by this strategy. An obvious route to take was to use the broad capping strategy successful for the tris(1,2—ethanediamine) complexes (ref. 1) and apply it to either tris(1,3-propanediamine) complexes or to sexidentate complexes of type 1:

Synthesis of a new cage ligand, SarAr, and its complexation with selected transition metal ions for potential use in radioimaging

A new hexaazamacrobicyclic cage ligand, 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine (SarAr) has been designed for conjugation to proteins. SarAr was synthesised and characterised by microanalyses, 1H NMR and electrospray mass spectrometry. The complexation of selected transition metal ions (Cu(II), Ni(II) and Co(II) at 10−6 M) by SarAr was complete within 30 min over pH 6 to 8. The [64Cu(SarAr)]2+ complex was investigated with a view to applications in radioimaging. The [64Cu(sar)]2+ complex was found to be stable in human plasma for at least 174 h and biodistribution studies in mice, showed that the [64Cu(SarAr)]2+complex was rapidly excreted through the renal system unlike the free 64Cu2+. Overall, the simple synthesis, ready complexation behaviour of SarAr, the kinetic inertness of the [Cu(SarAr)]2+ complex to dissociation of 64Cu and its facile elimination from mice make it an attractive prospect for use in nuclear medicine.

Macrotricyclic hexaamine cage complexes of cobalt(III): synthesis, characterization and properties

Synthese au coordinat hexadente tris(amino-2 ethyl)-1,4,7 triaza-1,4,7 cyclononane et de [CoL] 3+ . Synthese des complexes ou L est egalement: amino-9 hexaazatricyclodocosane, heptaazatricyclodocosane. Etude de configuration et electrochimique

The ligand field 1A1-5T2 spin crossover with iron(II) encapsulated in hexa-amine cages

Abstract The encapsulation of transition metal ions by hexa-amine ligands of the sarcophagine type permits their electronic and spectroscopic properties to be studied in a magnetically dilute and kinetically inert environment. In particular, the saturated nature of the amine yields a cryptand of the innocent kind so that the ligand field absorption of the metal containing cages is not obscured by intense charge transfer bands. This paper presents the results of magnetic, vis-UV spectroscopic and NMR measurements on a series of hexa-aza Werner complexes of encapsulated divalent iron performed over a range of temperature. The data reveal that both low-spin and high-spin isomers of the iron(II) cages coexist in solution. The temperature dependence of the physical parameters is characteristic of a spin equilibrium between molecular states of 1A1g and 5T2g origin.

Macrobicyclic chromium(III) hexaamine complexes

Le compose cristallise dans le systeme monoclinique, groupe P2 1 /c avec Z=4. Coordination octaedrique autour du cation. Etude electrochimique et photochimique

Variations on a Cage Theme: Some Complexes of Bicyclic Polyamines as Supramolecular Synthons

Dedication: One of Alan Sargeson’s great abilities was to seek out knowledge on topics of which he was not the master from those people with the expertise. This led occasionally to publications with a ‘cricket team’ of authors but with a rich brew of information, often international. Alan also insisted that all authors were equal since, without any one, the paper would not be what it was. Hence, he endeavoured to pursue the policy, difficult to maintain over a period where an obsession with absurdities such as the order of authors and point-scoring based on meaningless publication indices became so important in the maintenance of research, of listing authors simply in alphabetical order. In describing work begun while he was still with us, we have attempted to adhere to his principles. Analysis of a body of crystallographic information concerning metal(ii) and metal(iii) complexes of macrobicyclic hexamine ligands and some of their derivatives provides evidence for the action of a variety of intermolecular forces within the lattices. Hydrogen bonding is universal and its forms depend strongly upon the oxidation state and the particular nature of the metal ion bound to the macrobicycle. The introduction of both aliphatic and aromatic substituents leads to lattices in which these substituents associate, although, in the case of aromatic substituents, this is not necessarily a consequence of ‘π-stacking’, despite the fact that the aromatic ring planes form parallel arrays. At least in the case of CoIII, stable enantiomers of the complexes can be obtained, and in {Δ-(+)589-[Co{(NH3)(CH3)sar}]}2Cl2(C6(CO2)6)·26H2O (sar = 3,6,10,13,16,19-hexa-azabicyclo[6.6.6]icosane), the benzene hexacarboxylate anion adopts a chiral conformation in the presence of the optically active cation.

Novel cationic surfactants derived from metal ion cage complexes: potential anthelmintic agents

The synthesis of stable highly charged cationic detergents derived from metal ion cage complexes is described along with some of their properties and effects on helminth membranes.

Octahedral substitution mechanisms and reactive intermediates

The paper reviews and discusses some aspects of substitution of octahedral complexes in aqueous solution. The areas considered primarily are anation, aquation and substitution in labile and kinetically robust systems. The evidence for the existence of intermediates of reduced coordination number, the characteristics and properties of such intermediates and the implications of these properties in the aforementioned processes are considered. A discussion of some primary aspects of base hydrolysis in octahedral complexes is included. The intermediates derived from these processes and details concerning their lifetime and structure are discussed. Finally, the use of such intermediates for synthesis of labile and thermodynamically unstable products is exemplified. The dissociative character of all this chemistry is offset against the comparative absence of nucleophilic characteristics. The point is made that the absence of nucleophilic paths for electronically rich systems should lead more commonly to the observation of electrophilic reactions and some of the evidence for these is presented.

A manganese-chloride cluster as the functional centre of the O2 evolving enzyme in photosynthetic systems

Photosynthetic O2 evolution O2 evolving complex mechanism Manganese Chloride Metal cluster