Pharmacokinetic andin vivo evaluation of a self-assembled gadolinium(III)-iron(II) contrast agent with high relaxivity

Abstract

A high-molecular weight tetrametallic supramolecular complex [(Ln-DTPA-phen)3Fe]- (Ln = Gd, Eu, La) has been obtained upon self-assembly around one iron(II) ion of three 1,10-phenantroline-based molecules substituted in 5'-position with the polyaminocarboxylate diethylenetriamine-N,N,N',N',N'-pentaacetate, DTPA-phen(4-). The ICP-MS measurements indicated that the lanthanide:iron ratio is 3:1. Photoluminescence spectra of [Eu-DTPA-phen](-) and of [(Eu-DTPA-phen)3Fe]- are nearly identical, implying that the first coordination sphere of the lanthanide(III) ion has not been changed upon coordination of phenantroline unit to iron(II) ion. NMRD measurements revealed that at 20 MHz and 310 K the relaxivity of the [(Gd-DTPA-phen)3Fe]- is equal to 9.5 +/- 0.3 s(-1) mM(-1) of Gd (28.5 s(-1) per millimole per liter of complex) which is significantly higher than that for Gd-DTPA (3.9 s(-1) mM(-1)). The pharmacokinetic parameters of [(Gd-DTPA-phen)3Fe]- in rats indicate that the elimination of [(Gd-DTPA-phen)3Fe]- is significantly slower than that of Gd-DTPA and is correlated with a reduced volume of distribution. The low volume of distribution and the longer elimination time (T(e1/2)) suggest that the agent is confined to the blood compartment, so it could have an important potential as a blood pool contrast agent. The biodistribution profile of [(Gd-DTPA-phen)3Fe]- 2 h after injection indicates significantly higher concentrations of [(Gd-DTPA-phen)3Fe]- as compared with Gd-DTPA in kidney, liver, lungs, heart and spleen. The images obtained on rats by MR angiography show the enhancement of the abdominal blood vessels. The signal intensity reaches a maximum of 55% at 7 min post-contrast and remains around 25% after 90 min. MRI-histomorphological correlation studies of [Gd-DTPA-phen]- and [(Gd-DTPA-phen)3Fe]- showed that both agents displayed potent contrast enhancement in organs including the liver. The necrosis avidity tests indicated that, in contrast to the [Gd-DTPA-phen](-) precursor complex, the supramolecular complex [(Gd-DTPA-phen)3Fe]- exhibits necrosis avidity.

Classification and basic properties of contrast agents for magnetic resonance imaging

“…The strong signal enhancement enables imaging of nuclei other than protons, e.g. 3 He, 129 Xe, 13 C, 15 N, 6 Li, and their molecular distribution in vivo can be visualized in a clinically relevant time window (153).…”

“…The nuclear spin polarization of the noble gas isotopes 3 He and 129 Xe can be increased by four to five orders of magnitude using optical pumping, a process in which light is used to raise (or 'pump') the nuclear spins of the gas molecules from a lower energy level to a higher one, so as to achieve the population inversion characteristic of the hyperpolarized (HP) state. This new technology of hyperpolarized gas MRI holds enormous potential for enhancing sensitivity and contrast in pulmonary imaging.…”

“…These include diamagnetic agents, such as oral agents or the CEST agents initially proposed. Another family of agents recently used in MRI are the dynamic nuclear polarization (DNP) agents, such as hyperpolarized noble gases ( 3 He, 129 Xe) and 13 C-labeled organic compounds or ions like 6 Li þ . The strong signal enhancement from the probe's nuclei with long T 1 values allows the direct imaging of the probe's molecular distribution (a kind of positive contrast), thus making this MRI technique similar (and competitive) to other molecular imaging techniques such as positron emission tomography (PET).…”

Activatable T 1 and T 2 Magnetic Resonance Imaging Contrast Agents

“…For instance, Parac-Vogt et al describe an MRI probe, Gd-DTPA-phen, that self-assembles 3:1 with an Fe 2+ ion 58. The supramolecular complex, [(Gd-DTPA-phen) 3 Fe] − , has a relaxivity of 9.5 mM −1  s −1 as compared to 3.9 mM −1  s −1 for Gd-DTPA.…”

Smart MR Imaging Agents Relevant to Potential Neurologic Applications

“…The slower elimination of the compound from rats as compared with Gd-DTPA was found to correlate with a reduced volume of distribution and suggests that the complex is confined to the blood compartment. 42 Another strategy to detect Fe 2ϩ ions uses a molecule including 3 Gd 3ϩ -containing moieties linked together by a trishydroxamate unit, which is a strong binding agent for Fe 2ϩ . This approach relies on a concept similar to that schematized in Fig 4B; however, here the Gd 3ϩ complexes can be found in 1 molecular entity.…”