Alessandra Viale

Challenges for Molecular Magnetic Resonance Imaging

3.3. Magnetic Particle Imaging 3029 4. Challenges for CEST Agents 3029 4.1. Technical Issues 3029 4.2. Chemical Issues 3031 4.3. Biological Issues 3032 5. Challenges for Heteronuclear MR Imaging 3033 5.1. F-Based Probes 3033 6. Challenges for Hyperpolarized Probes 3034 6.1. Brute Force 3034 6.2. Optical Pumping and Spin Exchange 3035 6.3. Dynamic Nuclear Polarization (DNP) 3035 6.4. para-Hydrogen Induced Polarization (PHIP) 3037 6.5. Use of Gd Contrast Agents with Hyperpolarized Substances 3038

Current concepts on hyperpolarized molecules in MRI.

Hyperpolarization provides a strong enhancement of the MR signal and allows the acquisition of images from nuclei other than protons. Besides vascular imaging and perfusion studies the use of hyperpolarized molecules has allowed the visualization of real-time substrate uptake and metabolism in vivo. Metabolic imaging is an outstanding field of research that aims at providing the clinicians with the possibility of interrogating real-time complex metabolic pathways that give a direct insight into the cellular state and activity.

Para-hydrogenated Glucose Derivatives as Potential 13C-Hyperpolarized Probes for Magnetic Resonance Imaging

A set of molecules in which a glucose moiety is bound to a hydrogenable synthon has been synthesized and evaluated for hydrogenation reactions and for the corresponding para-hydrogen-induced polarization (PHIP) effects, in order to select suitable candidates for an in vivo magnetic resonance imaging (MRI) method for the assessment of glucose cellular uptake. It has been found that amidic derivatives do not yield any polarization enhancement, probably due to singlet-triplet state mixing along the reaction pathway. In contrast, ester derivatives are hydrogenated in high yield and afford enhanced (1)H and (13)C NMR spectra after para-hydrogenation. The obtained PHIP patterns are discussed and explained on the basis of the calculated spin level populations in the para-hydrogenated products. These molecules may find interesting applications in (13)C MRI as hyperpolarized probes for assessing the activity of glucose transporters in cells.

SYNTHESIS, CHARACTERIZATION AND DNA BINDING AFFINITIES OF WATER-SOLUBLE BENZOHETEROCYCLE TRIOSMIUM CLUSTERS

The syntheses of the water-soluble clusters [Os3(CO)9(μ-η2-(LH))(μ-H)L′] (L=3-amino quinoline, L′=Na3[P(C6H4SO3)3] 1; L=3-amino quinoline, L′=[P(OCH2CH2NMe3)3]I3, 2; L=3-(2-phenyl acetimido) quinoline, L′=[P(OCH2CH2NMe3)3]I3, 3; L=phenanthridine, L′=[P(OCH2CH2NMe3)3]I3, 4) are reported. The products have been fully characterized by 1H-, 13C VT-NMR and LC–TOF-MS. The effect of pH and concentration on intermolecular aggregation in water has been investigated. The interactions of these clusters with DNA have been studied using the plasmid super coiled DNA relaxation test in a 1% electrophoresis agarose gel. Band retardation due to cluster binding was observed for the positively charged clusters 2–4, but not for the negatively charged 1. The relative binding affinities were in the order 2<3∼4 and all three showed greater binding affinities than the positively charged cluster [Rh3(μ3-S)2(η5-Me5C5)3](BF4)2. These preliminary results suggest a relationship between the nature of the heterocyclic ligand and the binding affinity of the cluster to DNA.

15N Magnetic Resonance Hyperpolarization via the Reaction of Parahydrogen with 15N-Propargylcholine

(15)N-Propargylcholine has been synthesized and hydrogenated with para-H(2). Through the application of a field cycling procedure, parahydrogen spin order is transferred to the (15)N resonance. Among the different isomers formed upon hydrogenation of (15)N-propargylcholine, only the nontransposed derivative contributes to the observed N-15 enhanced emission signal. The parahydrogen-induced polarization factor is about 3000. The precise identification of the isomer responsible for the observed (15)N enhancement has been attained through a retro-INEPT ((15)N-(1)H) experiment. T(1) of the hyperpolarized (15)N resonance has been estimated to be ca. 150 s, i.e., similar to that reported for the parent propargylcholine (144 s). Experimental results are accompanied by theoretical calculations that stress the role of scalar coupling constants (J(HN) and J(HH)) and of the field dependence in the formation of the observed (15)N polarized signal. Insights into the good cellular uptake of the compound have been gained.

Agents for Polarization Enhancement in MRI

The intrinsic low sensitivity of the NMR phenomenon can be overcome thanks to hyperpolarization procedures that break the limits of the Boltzmann equilibrium and may increase the NMR signal by a factor of 10(5). Hyperpolarization procedures have been applied to enhance the signal from noble gases, such as 3He and 129Xe, and small 13C-containing molecules. For the latter class, attention has been focused on the use of methods based on dynamic nuclear polarization (DNP) and para-hydrogen induced polarization (PHIP). After discussion of the basics of the methods, an overview of the main applications with 13C-containing molecules is presented. This includes pre-clinical MR investigations of vascular imaging, perfusion and catheter tracking as well as molecular imaging protocols that allow the development of highly innovative studies in the field of metabolic imaging.

Ligand dependent structural changes in the acid-base chemistry of electron deficient benzoheterocycle triosmium clusters

Abstract The reactions of the electron deficient benzoheterocycle clusters Os3(CO)9(μ3-η2-LH)(μ-H) (L=phenanthridine, 2; 5,6-benzoquinoline, 3; quinoxaline, 4; 2-methyl benzimidazole, 5; 2-methyl benzotriazole, 6; 2-methyl benzothiazole, 7; benzothiazole, 8; 2-methyl benzoxazole, 9; benzoxazole, 10) with n-butylamine and with the protic acids HBF4 and CF3CO2H are reported. Complexes 2 and 3 behave very similarly to the analogous quinoline complex (L=quinoline, 1) forming adducts with n-butylamine with similar spectral properties to 1 and undergoing simple protonation at the metal core with both HBF4 and CF3CO2H. Complexes 4–10 on the other hand form an additional amine adduct with different spectral characteristics than 1–3 and in the case of 5 this is the only detectable product. In addition, these compounds also form adducts with acetonitrile while 1–3 do not. Compounds 4–9 also exhibit much more complex behavior in the presence of CF3CO2H than 1–3, giving trifluoroacetate adducts subsequent to initial protonation. Although 4, 5 and 10 behave differently than 1 with n-butylamine and protic acids they form exactly the same triphenyl phosphine adduct as 1 and 3 based on multinuclear NMR data. The solid-state structure for the amine adduct of 2 is reported and suggested structures for the other amine and acid adducts, based on NMR data, are presented. The reasons for the differences in the behavior of the three distinct groups of benzoheterocycles (1–3, 4 and 5–10) are discussed.

How to design 13C para-hydrogen-induced polarization experiments for MRI applications

The application of hyperpolarization techniques for MRI purposes is gathering increasing attention, especially for nuclei such as (13)C or (129)Xe. Among the different proposed methods, ParaHydrogen Induced Polarization requires relatively cheap equipment. The setup of an MRI experiment by means of parahydrogen requires the application of skills and methodologies that derive from different fields of knowledge. The basic theory and a practical insight of this method are presented here. Parahydrogenation of alkynes, having a labelled (13)CO group adjacent to the triple bond, catalyzed by Rh(I) complexes containing a chelating phosphine, represents the best choice for producing and maintaining high heteronuclear polarization effect. In order to transform anti-phase into in-phase (net) (13)C polarization for MRI application it is necessary to set up the described magnetic field cycle procedure. In vitro and in vivo images have been acquired using fast imaging sequences (RARE and trueFISP).

15N-permethylated amino acids as efficient probes for MRI-DNP applications.

The synthesis, NMR properties and preliminary polarization tests on protonated and perdeuterated forms of α-trimethylglutamine (NMe3Gln), α-trimethylglutamate (NMe3Glu) and ε-trimethyllysine (NMe3Lys) are reported. The (15)N-permethylated, perdeuterated amino acids display very long (15)N-T1 values, ranging between 190 and 330 s, are well polarized by the dynamic nuclear polarization (DNP) procedure, yielding good polarization levels (10%), and appear to be well tolerated by cells and mice. The obtained results make perdeuterated amino acids excellent candidates for innovative DNP (15)N-MRI applications such as perfusion or targeting studies.

Conformational constraints and σ–π-vinyl interchange in μ3-η3-5,6-dihydroquinoline triosmium complexes

Abstract The rates of the σ–π-interchange processes in the series of 5,6-dihydro-μ 3 -η 3 -quinolyl complexes Os 3 (CO) 9 (C 9 H 6 (5-R,6-R′)N)(μ-H) (R=R′=H, 1 , R= n Bu, R′=H, 2 ; R=allyl, R′=CH 3 , 3 , R=C(CH 3 ) 2 CN, R′=CH 3 , 4 ; R=CHS(CH 2 ) 2 S, R′=CH 3 , 5 ; R=CH 2 CO 2 t Bu, R′=CH 3 , 6 ; R=CH 2 CO 2 t Bu, R′=Cl, 7 ) have been examined by 1 H-NMR spectroscopy using the 187 Os 1 H satellites as a dynamical probe. It was found that the unsubstituted and monosubstituted derivatives 1 and 2 are dynamic with respect to the σ-π-interchange process throughout the temperature range examined (+25 to −80°C). The disubstituted derivatives 3 – 6 on the other hand are rigid on the NMR time scale up to +100°C where coalescence of the satellites is observed. For compound 7 , the barrier to σ–π-interchange is intermediate between 1 and 2 and 3 – 6 , exhibiting coalescence at +70°C. Compound 7 also exhibits evidence for population of a second isomer as observed from VT 1 H-NMR of the vinylic proton. The results are discussed in the context of the conformational constraints around the 5,6-carbon–carbon bond of the carbocyclic ring in these dihydroquinolyl complexes and are compared with previously reported σ–π-vinyl interchange processes.