Unprecedented Kinetic Inertness for a Mn²⁺‐Bispidine Chelate: A Novel Structural Entry for Mn²⁺‐Based Imaging Agents

Abstract

The search for more biocompatible alternatives to Gd 3+-based MRI agents,a nd the interest in 52 Mn for PET imaging call for ligands that form inert Mn 2+ chelates.G iven the labile nature of Mn 2+ ,h igh inertness is challenging to achieve.The strongly preorganized structure of the 2,4-pyridyldisubstituted bispidol ligand L 1 endows its Mn 2+ complex with exceptional kinetic inertness.I ndeed, MnL 1 did not showa ny dissociation for 140 days in the presence of 50 equiv.o fZ n 2+ (37 8 8C, pH 6), while recently reported potential MRI agents MnPyC3A and MnPC2A-EA have dissociation half-lives of 0.285 ha nd 54.4 hu nder similar conditions.I na ddition, the relaxivity of MnL 1 (4.28 mm À1 s À1 at 25 8 8C, 20 MHz) is remarkable for am onohydrated, small Mn 2+ chelate.I nvivo MRI experiments in mice and determination of the tissue Mn content evidence rapid renal clearance of MnL 1 .Additionally, L 1 could be radiolabeled with 52 Mn and the complex revealed good stability in biological media.

Expanding the Ligand Classes Used for Mn(II) Complexation: Oxa-aza Macrocycles Make the Difference

“…One of the most widely explored alternatives relies on the use of high-spin Mn(II) complexes, which present similar abilities to enhance 1 H relaxation of water nuclei as analogous Gd(III) complexes [10][11][12]. The main challenge to develop Mn(II)-based contrast agents relies on the difficulties to obtain thermodynamically stable and kinetically inert complexes, to avoid the release of the potentially toxic metal ion [13], while leaving a coordination position available for a water molecule [14]. The inner-sphere water molecule exchanges with bulk water, which provides an efficient mechanism for the relaxation of water 1 H nuclei in the vicinity of the agent [15].…”

Metal ion size profoundly affects H3glyox chelate chemistry

“…It has been noted previously that a rigid scaffold such as bispidine around the Mn 2+ ion endows the manganese complex with increased kinetic inertness and similar to 10 No data on apparent molar activities for 52g Mn-labeled complexes were found in the literature for other chelators discussed here for comparison. 10,36 Radiolabeling with [ 177 Lu]LuCl 3 Encouraged by the relatively high pM value (pLu ¼ 18.1), preliminary radiolabeling studies were done to investigate the complexation kinetics of the hexadentate chelator H 3 glyox with [ 177 Lu]LuCl 3 . Although Lu 3+ ion is a larger trivalent metal ion with an ionic radius of 86-103 pm and coordination number 6-9, 17 the mismatch with the cavity size of H 3 glyox is evident from the observed RCYs.…”

Complexation of Mn(II) by Rigid Pyclen Diacetates: Equilibrium, Ki-netic, Relaxometric, DFT and SOD Activity Studies.

“…20 The most inert Mn(II) complex was recently described by É Tóth et al, which is a Mn(II) chelate formed with a 2,4-pyridyl-disubstituted bispidol ligand. 8 Our recent studies performed with trisubstituted cyclododecane derivatives have revealed greater conditional stability for [Mn(PCTA)]than for [Mn(DOTA)] 2-(at pH=7.4). 16 The kinetic inertness of [Mn(PCTA)]is sufficiently high to allow for further ligand modification, such as reduction of ligand denticity to allow the coordination of a water molecule to the metal ion.…”

“…Among the recently studied systems there are very few inert Mn(II) complexes. 8 Within the group of open-chain ligands, the rigid CDTA 9 and its derivatives (i.e. PyC3A) 10 or PhDTA 11 complexes (Chart 1) display the best features.…”