Hermann Scharfetter1, Christian Gösweiner1, Evrim Umut2, Carina Sampl3, Roland Fischer3, Stefan Spirk4, Andreas Petrovic1, and Danuta Kruk2
1Institute of Medical Engineering, Graz University of Technology, Graz, Austria, 2Faculty of Mathematics and Computer Science, Universtiy of Warmia and Mazury, Olsztyn, Poland, 3Institute for Chemistry and Technology of Materials, Graz University of Technology, Graz, Austria, 4Institute of Paper, Pulp and Fibre Technology, Graz University of Technology, Graz, Austria
Synopsis
209Bi-aryl compounds have the potential for designing novel class of smart MRI T1
contrast agents which are sensitive to the chemical environment and the B0
field. We have confirmed quadrupolar relaxation enhancement (QRE) of protons as
the underlying mechanism in two solid organobismuth-compounds in the B0
range 0.5 – 3T. We also show first QRE peaks of solvent
protons in a solution of Tris-(2-orthomethoxy-Phenyl)Bismuthane in tetrahydrofurane. This very
important first step yields two promising
candidates for the development of QRE-based CAs and opens the way for the
second step, i.e. grafting them onto water-soluble nanoparticles for optimizing the relaxivity.
INTRODUCTION
High spin
quadrupolar nuclei (QN) such as 209Bi have the potential to provide quadrupolar
T1 relaxation enhancement (QRE) of protons and can serve as cores of
a entirely novel class of MRI T1 contrast agents (CA)1.
Condition
for QRE is a high probability for quantum-mechanical transitions of the 209Bi
at the 1H Larmor frequency fL or its second harmonic 2fL.
In this case the magnetization transferred from 1H to 209Bi by fluctuating dipole-dipole
coupling (DDC) is efficiently relaxed by the QN’s quadrupolar relaxation2.
The effect depends on flux density B0 , proton exchange rate, the motional
dynamics of the molecule and the electric
field gradient (EFG) caused by the chemical bonding structure of the QN. Therefore
QRE can enable smart CAs for molecular MRI by switching on and off the contrast
either by B0 shifts or by chemical interaction with the biological
environment.
As important
steps towards a QRE based CA we (1)
pre-selected two promising organo-Bismuth-compounds and determined their
quadrupole transition frequencies QTF by Nuclear Quadrupole Resonance
Spectroscopy (NQRS), (2) identified QRE in solid powders by Fast Field Cycling
NMR spectroscopy (FFC-NMRS) and (3) observed for the first time QRE in solution. The solid QRE spectra were interpreted with a quantum-mechanical
model for the expected transition probabilities.
METHODS
Tris-(2-orthomethoxy-Phenyl)Bismuthane
and Tris-(2,6-Diorthomethoxy-Phenyl)Bismuthane
were synthetized and checked for purity by NMR spectroscopy. Their
quadrupolar coupling constant Qcc
and asymmetry parameter
η
were determined from their QTF by NQRS with a
Tecmag Scout spectrometer and custom-built
coils3. FFC-NMRS was carried out on a STELAR Spinmaster
relaxometer equipped with a magnet operating up to 3T, at frequencies 20MHz – 128MHz (ca. 0.5 – 3T). For comparison
with the FFC-NMRS data a simple quantum-mechanical model was employed: Because
of the absence of rotations in the solid the energy level structure of the Bi
was assumed to be static. The spectral density of DDC by the remaining modes of
molecular motion was considered as frequency-independent. Thus we calculated
the quantum-mechanical transition probabilities TP(B0) between
energy eigenstates of the 209Bi at fL and 2fL
(corresponding to single and double 1H quantum transitions) from Qcc
and η. The angle-depencence of QRE was considered by
integrating over a spherically uniform random distribution of the EFG
orientation, as expected in powders. Results were presented in normalized form TPnorm=TP(B0)/max(TP).RESULTS
Fig.
1A shows peaks of R1 labelled I – V in the measured R1(B0)
of (Tris-(2-orthomethoxy-Phenyl)Bismuthane.
The simulated TPnorm for 209Bi transitions at fL
in fig. 1B shows a very similar pattern with the same peak locations except for
a slight downshift of peak II. TPnorm at 2fL in fig. 1C is
expected to contribute much more weakly to R1 because of the
much lower probability for 1H double quantum transitions. However, the
weak features labelled with ‘X’ may be due to such transitions. The steep
increase of the relaxation rate below 0.2T is due to dipolar proton-proton
interaction which is known to cause strong background relaxation at low B0.
Fig. 2 shows the same information for Tris-(2,6-diorthomethoxy-Phenyl)Bismuthane.
The measured peaks III- IV again occur at the frequencies of high TPnorm
for single fL. Peak II appears upshifted in the simulation and
feature ‘Y’ coincides only with the edge of a peak in fig. 2.C, i.e. a 1H
double quantum transition.Discussion
Despite
strong model simplifications the agreement between simulated and experimentally
observed peaks is very good and confirms QRE of intrinsic protons in two solid
organo-Bismuth compounds. We thus consider them as promising candidates for showing
QRE after grafting them onto nanoparticles which can be dispersed in water. Preliminary
FFC-NMRS data of a solution of (Tris-(2-orthomethoxy-Phenyl)Bismuthane in tetrahydrofurane (THF) at -73°C in fig. 3B show two clear broad peaks L2 and L4
and two smaller ones (L1, L3) at B0 > 1.5T. Their locations are close to but
not identical with those of peaks IV and V of the solid (fig 3A), which is to be
expected due to fast rotation of the particles in solution.CONCLUSION
To
our knowledge we have successfully demonstrated, for the first time, QRE in two
selected solid organobismuth compounds. Moreover we found QRE in a solution of
(Tris-(2-orthomethoxy-Phenyl)Bismuthane in THF. Remarkeably the last peak
occurs at 2.7T, i.e. close to the clinical 3T. Though the effect in the
liquid is still small due to strongly suboptimal particle dynamics, this is an
important step towards the development of QRE based T1 CAs. The next
steps are the preparation of suitable nanoparticles for the maximization of the
relaxivity and tuning to concrete clinical field strengths.Acknowledgements
This project has received funding from the European Union’s Horizon 2020 research and innovation
programme under grant agreement No 665172.References
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Nuclear Quadrupole Enhanced Relaxation: Principle, Requirements and
Characterization of Promising Compounds’, Proc.
Intl. Soc. Mag. Reson. Med. 25, 3058, 2017.
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