Taylor dispersion analysis for measurement of diffusivity and size of gadolinium-based contrast agents.

Gadolinium-based contrast agents (GBCA) are complexes of a Gadolinium metal center and a linear or macrocyclic polyamino-carboxylic acid chelating agent. These agents are employed to enhance the visibility of deep abnormalities through MRI techniques. Knowing the precise dimensions of various GBCA is key parameter for understanding their in-vivo and pharmaco-kinetic behaviors, their diffusivity, as well as their relaxivity.

Exploring the Limits of Ligand Rigidification in Transition Metal Complexes with Mono--Functionalized Pyclen Derivatives.

We report the synthesis of a new family of side-bridged pyclen ligands. The incorporation of an ethylene bridge between two adjacent nitrogen atoms was reached from the pyclen-oxalate precursor described previously. Three new side-bridged pyclen macrocycles, H, , and H, were obtained with the aim to assess their coordination properties toward Cu and Zn ions.

Versatile Macrocyclic Platform for the Complexation of [Y/Y]Yttrium and Lanthanide Ions.

We report a macrocyclic ligand (H) based on a 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane platform containing three acetate pendant arms and a benzyl group attached to the fourth nitrogen atom of the macrocycle. The X-ray structures of the Y and Tb complexes reveal nine coordination of the ligand to the metal ions through the six nitrogen atoms of the macrocycle and three oxygen atoms of the carboxylate pendants. A combination of NMR spectroscopic studies (H, C, and Y) and DFT calculations indicated that the structure of the Y complex in the solid state is maintained in an aqueous solution.

Tuning the lipophilic nature of pyclen-based 90Y3+ radiopharmaceuticals for β-radiotherapy.

Pyclen-dipicolinate chelates proved to be very efficient chelators for the radiolabeling with β--emitters such as 90Y. In this study, a pyclen-dipicolinate ligand functionalized with additional C12 alkyl chains was synthesized. The radiolabeling with 90Y proved that the addition of saturated carbon chains does not affect the efficiency of the radiolabeling, whereas a notable increase in lipophilicity of the resulting 90Y radiocomplex was observed.

Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Gadolinium Complexation.

We report the synthesis of two pyclen-based regioisomer ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with picolinic acid pendant arms either at positions () or () of the macrocyclic fragment.

Expanding the Scope of Pyclen-Picolinate Lanthanide Chelates to Potential Theranostic Applications.

A family of three picolinate pyclen-based ligands, previously investigated for the complexation of Y and some lanthanide ions (Gd, Eu), was studied with Tb and Lu in view of potential radiotherapeutic applications. The set of six Tb and Lu complexes was synthesized and fully characterized. The coordination properties in the solid state and in solution were thoroughly studied.

Physicochemical and Pharmacokinetic Profiles of Gadopiclenol: A New Macrocyclic Gadolinium Chelate With High T1 Relaxivity.

Objectives: We aimed to evaluate gadopiclenol, a newly developed extracellular nonspecific macrocyclic gadolinium-based contrast agent (GBCA) having high relaxivity properties, which was designed to increase lesion detection and characterization by magnetic resonance imaging.

Methods: We described the molecular structure of gadopiclenol and measured the r1 and r2 relaxivity properties at fields of 0.47 and 1.

Expanding the Family of Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Lanthanide Complexation.

We report a detailed characterization of lanthanide complexes with two azaligands based on the pyclen macrocycle containing two picolinate and one acetate pendant arms. The two picolinate arms are attached to either opposite (L3) or adjacent (L4) amine nitrogen atoms of the macrocyclic platform. The X-ray structures of the Yb complexes show nine coordination of the ligand to the metal ion, a situation that is also observed for EuL4 in the solid state.

Stable and Inert Yttrium(III) Complexes with Pyclen-Based Ligands Bearing Pendant Picolinate Arms: Toward New Pharmaceuticals for β-Radiotherapy.

We report the synthesis of two azaligands based on the pyclen macrocyclic platform containing two picolinate and one acetate pendant arms. The two ligands differ in the relative positions of the pendant functions, which are arranged either in a symmetrical (L3) or nonsymmetrical (L4) fashion. The complexation properties of the ligands toward Y and Y were investigated to assess their potential as chelating units for radiopharmaceutical applications.

A Coordination Chemistry Approach to Fine-Tune the Physicochemical Parameters of Lanthanide Complexes Relevant to Medical Applications.

The geometric features of two pyclen-based ligands possessing identical donor atoms but different site organization have a profound impact in their complexation properties toward lanthanide ions. The ligand containing two acetate groups and a picolinate arm arranged in a symmetrical fashion (L1) forms a Gd complex being two orders of magnitude less stable than its dissymmetric analogue GdL2. Besides, GdL1 experiences a much faster dissociation following the acid-catalyzed mechanism than GdL2.

The role of the capping bond effect on pyclen Y/Y chelates: full control of the regiospecific N-functionalization makes the difference.

Thanks to a smart regiospecific N-functionalization, a pyclen based ligand bearing one picolinate and two acetate arms organized in a dissymmetric manner was synthesized for Y complexation, and compared to its symmetric analogue. The nature of the capping bonds around the metal coordination environment has a dramatic effect on the properties of the chelate, the Y and Y dissymmetric derivatives presenting enhanced thermodynamic stability and kinetic inertness.

Pyclen Tri-n-butylphosphonate Ester as Potential Chelator for Targeted Radiotherapy: From Yttrium(III) Complexation to (90)Y Radiolabeling.

The Y(3+) complex of PCTMB, the tri-n-butyl phosphonate ester of pyclen (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene), was synthesized as well as its Ho(3+) and Lu(3+) analogues.

Early detection of colonic dysplasia by magnetic resonance molecular imaging with a contrast agent raised against the colon cancer marker MUC5AC.

Human gastric mucin MUC5AC is secreted in the colonic mucus of cancer patients and is a specific marker of precancerous lesions called aberrant crypt foci. Using MUC5AC as a specific marker can improve sensitivity in the detection of early colorectal cancer. Here we demonstrated that the accumulation of MUC5AC in xenograft and mouse stomach can be detected by magnetic resonance imaging (MRI).

A new (68)Ga anionic concentration and purification method for automated synthesis of [(68)Ga]-DOTA or NODAGA conjugated peptides in high radiochemical purity.

The (68)Ge/(68)Ga generator is of increasing interest for clinical PET. For successful labelling, the eluate has to be purified. The aim of our approach is to improve the existing anionic methods which have a number of advantages compared to other methods but which use high concentrated HCl, and require an additional anionizing step.

Development of a magnetic resonance imaging protocol for the characterization of atherosclerotic plaque by using vascular cell adhesion molecule-1 and apoptosis-targeted ultrasmall superparamagnetic iron oxide derivatives.

Objective: Acute ischemic events are often caused by the disruption of lipid-rich plaques, which are frequently not angiographically visible. Vascular cell adhesion molecule-1 and apoptotic cell-targeted peptides studied during our previous work were conjugated to ultrasmall superparamagnetic iron oxide (USPIO) (USPIO-R832 for vascular cell adhesion molecule-1 targeting; USPIO-R826 for apoptosis targeting) and assessed by magnetic resonance imaging.

Methods And Results: Apolipoprotein E knockout mice were injected with 0.

In vitro biomedical applications of functionalized iron oxide nanoparticles, including those not related to magnetic properties.

Superparamagnetic iron oxide nanoparticles (SPION) are very promising contrast media, especially for molecular imaging, due to their superior NMR efficacy. They even have wider biomedical applications such as in drug and gene delivery, tissue engineering and bioseparation, or as sensitive biological nanosensors. By coupling them to affinity ligands, SPION can bind to drugs, proteins, enzymes, antibodies or nucleotides.

Synthesis and evaluation of a tri-tyrosine decorated dextran MR contrast agent for vulnerable plaque detection.

This communication reports the synthesis, characterization and in vivo evaluation in mice of a new tri-tyrosine conjugated MR contrast agent, which may help to identify vulnerable plaques in atherosclerosis by targeting the lipid core.

Peptidic targeting of phosphatidylserine for the MRI detection of apoptosis in atherosclerotic plaques.

Molecular and cellular imaging of atherosclerosis has garnered more interest at the beginning of the 21st century, with aims to image in vivo biological properties of plaque lesions. Apoptosis seems an attractive target for the diagnosis of vulnerable atherosclerotic plaques prone to a thrombotic event. The aim of the present work was to screen for apoptosis peptide binders by phage display with the final purpose to detect apoptotic cells in atherosclerotic plaques by magnetic resonance imaging (MRI).

Magnetic resonance molecular imaging of vascular cell adhesion molecule-1 expression in inflammatory lesions using a peptide-vectorized paramagnetic imaging probe.

The vascular cell adhesion molecule-1 (VCAM-1) has distinct roles in inflammatory cell recruitment to the damaged vessel wall. In the present work, a cyclic heptapeptide phage displayed library was screened in vitro during four rounds of biopanning. On the basis of Kd and IC50 values, a peptide (encoded as R832) was selected for in vitro and in vivo validation.

Biomimetic MRI contrast agent for imaging of inflammation in atherosclerotic plaque of ApoE-/- mice: a pilot study.

Objective: Atherosclerosis involves an inflammatory process characterized by cellular and molecular responses. A slow-clearance blood-pool paramagnetic agent (CMD-A2-Gd-DOTA: P717) chemically modified to create a functionalized product (F-P717) for targeting inflammation in vessel walls was evaluated in vivo in mice.

Methods And Results: Carboxylate and sulfate groups were grafted onto the macromolecular paramagnetic Gd-DOTA-dextran backbone.

Evaluation of matrix metalloproteinases in atherosclerosis using a novel noninvasive imaging approach.

Objective: Despite great advances in our knowledge, atherosclerosis continues to kill more people than any other disease in the Western world. This is because our means of identifying truly vulnerable patients is limited. Prediction of atherosclerotic plaque rupture may be addressed by MRI of activated matrix metalloproteinases (MMPs), a family of enzymes that have been implicated in the vulnerability of plaques prone to rupture.