Optimization of Pentadentate Bispidines as Bifunctional Chelators for⁶⁴Cu Positron Emission Tomography (PET)

Abstract

Pentadentate bispidine ligands (3,7-diazabicyclo[3.3.1]nonanes) are optimized for maximum complex stability and facile functionalization with respect to their coupling to biological vector molecules and/or fluorescence markers for PET (positron emission tomography) and multimodal imaging (i.e., PET and optical imaging). The pentadentate ligand with two tertiary amine donors, two p-methoxy substituted pyridines, and one unsubsituted pyridine group is shown to best fulfill important conditions for PET applications, i.e., fast complexation with Cu(II) and high in vivo stability, and this was predicted from the solution chemistry, in particular the Cu(II/I) redox potentials. Also, solvent partition experiments to model the lipophilicity of the Cu(II) complexes indicate that the bis p-methoxy substituted ligand leads to cationic complexes with an appreciable lipophilicity. This is supported by the biodistribution experiments that show that the complex with the p-methoxy substituted ligand is excreted very quickly and primarily via the renal route and therefore is ideally suited for the development of PET tracers with ligands of this type coupled to biomolecules.

CuII-selective bispidine–dye conjugates

“…3 for the X-ray structures). It was expected that the Cu II -induced deprotonation of the amide occurs at pH values significantly lower than physiological [14][15][16][17], and then forms very stable Cu II complexes (CB2c, see Fig. 3).…”

“…Importantly, the alcohol group at C9 provides a further site for functionalization, which further increases the flexibility of the bispidine building block B1. However, unexpectedly [14][15][16][17], the chelating amide does not coordinate at physiological pH, and further studies in this area will concentrate at hexadentate bispidines using the C 9 -based alcohol as an anchor for conjugation to biological vectors and/or dye molecules [11].…”

“…The hypothesis was that functionalization of the pendant amine at N7 leads to an amide which, upon coordination of the bispidine derivative to Cu II would deprotonate and coordinate, and lead to additional stability of the Cu II complexes [14][15][16][17]. Therefore, the functionalized bispidine B1 (Scheme 1) with a free amine group at N 7 was prepared to enable a simple conjugation to fluorescent dyes, usually available as the NHS-ester derivatives.…”

“…Experimental structures of the molecular cations of the Cu II complexes CB2a and CB2b; also included is the published structure CB2c[14]. Complexes were either prepared with Cu(ClO 4 ) 2 in acetonitrile (CB2a), with Cu(OAc) 2 in methanol (CB2b) or with Cu(ClO 4 ) 2 in MeOH/OMe − ; ellipsoids at 30% probability; hydrogen atoms, counter ions and solvent molecules neglected; Cu yellow, N blue, O red, C grey.…”

Optimization of Hexadentate Bispidine Ligands as Chelators for 64CuII PET Imaging

“…Among other reasons, these arise from the rigid adamantane‐derived backbone—preorganized and complementary for tetragonally distorted octahedral geometries—that is well suited and selective for binding Cu II ; it is also for this reason that bispidines have been described as a favorable ligand platform for medicinal applications . In addition to radiopharmaceutical chemistry, applications of Cu–bispidines include aziridination catalysis, and hemocyanine and catecholase biomimetic chemistry …”