Gadolinium(III) Introduction to a Lanthanide MRI Contrast Agent Rinck P., Magnetic Resonance in Medicine

About Gd(III) Lanthanide, considered a “hard” acid Typical coordination number: 8 - 10 Paramagnetic, 7 unpaired electrons Roughly same size as Ca(II) ~ 0.99 Å → toxicity issue The Actinide Research Quarterly Elster, A. D., 2016 Gd0 electronic configuration

What Makes Gadolinium Different? Extracellular intravenous agent, in use since 1988 Paramagnetism is the main reason for the role of Gd(III) in MRI 9 coordination allows chelation specificity Tissue distinction, blood brain barrier permeability Chemical Name Product Name [Gd(DTPA)(H2O)]2- Magnevist [Gd(DOTA)(H2O)]- Dotarem [Gd(DTPA-BMA)(H2O)] Omniscan [Gd(HP-DO3A)(H2O)] ProHance [Gd(DO3A-butrol)(H2O)] Gadovist Magnevist Lauffer R. B, 1987 Dotarem Sherry, A. D.; et al. 2009

Some Gd(III) Chelates Cyclic Linear

Gd(III) Complexes [Gd(BOPTA)(H2O)]2- (MultiHance) [Gd(DOTA)(H2O)]- (Dotarem) [Gd(DOTA)(H2O)]- [Gd(DTPA)(H2O)]2- LogK = 24.7 LogK = 22.5 LogKeff, pH 7.4 = 17.2 LogKeff, pH 7.4 = 18.4 [Gd(DTPA)(H2O)]2- (Magnevist) Caravan, P.; et al. 1999 Sherry A. D.; et al. 2009

New Lanthanide Geometry Senn, F.; et al., 2012 [Gd(DOTA)(H2O)]- (Dotarem) Caravan, P.; et al. 1999

Importance of Water Exchange and Ligand Interaction of protons from water is key to contrast agent Inner sphere: many exchanges per second, bulk water interaction Ligand has effect on this exchange Outer sphere: H bonding from complex etc. [Gd(DTPA)]2- [Gd(DTPA)(H2O)]2- Inner Sphere [Gd(DTPA)(H2O)]2- Outer Sphere Elster, A. D., 2016

What Does an MRI Contrast Agent Do? MRI is NMR, signal is the reradiation of energy after perturbation of nuclei Greater proton (water) density, larger signal Paramagnetism decreases relaxation time, increasing signal intensity [Gd(DTPA)(H2O)]2- (Magnevist) Gilbert, P., 2013

What Does an MRI Contrast Agent Do? Gadolinium contrast agent decreases T1 relaxation time T1 and T2 relaxation times change with a paramagnetic agent present T1: decay to equilibrium parallel to magnetic field, Z component T2: decay to X and Y equilibrium T1-weighted T2-weighted Gd(III) Concentration: 1) None 2) Low 3) High Elster, A. D.; et al. 1990

Toxicity Similar size as calcium(II) can interrupt signalling if Gd(III) is not chelated Transmetallation can occur with other endogenous metals, displacing Gd(III) Fe(III), Cu(II), Zn(II) Zn(II) in highest concentrations Gadolinium can precipitate as a phosphate salt Nephrogenic Systemic Fibrosis (NSF) Prone to those with acute kidney injury/disease Swelling, tightening, thickening, hardening of skin Muscle weakness, bone pain Mayo Clinic

Current and Future Work in Gd(III) MRI Agents Understand toxicity mechanism Optimize relaxivity Ligand studies, molecular weight component Improve Targeting Antibody, protein coupling Functional agents Zhou, Z.; et al. 2013

Works Cited The Actinide Research Quarterly: 1st Quarter 2004 http://www.lanl.gov/orgs/nmt/nmtdo/AQarchive/04spring/VO.html Caravan, P.; Ellison, J. J.; Mcmurry, T. J.; Lauffer, R. B. Chemical Reviews 1999, 99 (9), 2293–2352. Direct Evidence of Gadolinium Deposition in Brain Tissues Following MRI Exams http://erean.eu/wordpress/direct-evidence-of-gadolinium-deposition-in-brain-tissues-following-mri-exams/ Elster, A. D.; Sobol, W. T.; Hinson, W. H. Radiology 1990, 174 (2), 379–381. Elster, A.D.; Gadolinium, 2016 http://mriquestions.com/why-gadolinium.html Gaillard, F.; Jones, J. MRI sequences (overview), Radiopaedia.org https://radiopaedia.org/articles/mri-sequences-overview Gilbert, P. ”Gadolinium Neutron Capture Therapy” 2013, http://home.physics.wisc.edu/gilbert/cancer.htm Johnson, K. A. MR Signal Sources http://www.med.harvard.edu/aanlib/sigsors.html Lauffer, R. B. Chemical Reviews 1987, 87 (5), 901–927. Moore, T. “T1 Decay” 2011, https://www.youtube.com/watch?v=A0dl4_wxr1c Nephrogenic systemic fibrosis Mayo Foundation for Medical Education and Research, 2016. http://www.mayoclinic.org/diseases-conditions/nephrogenic-systemic-fibrosis/more-about/in-depth/ssc-20204468 Rinck P. Magnetic Resonance in Medicine. The Basic Textbook of the European Magnetic Resonance Forum. 2016. Electronic version 10. Senn, F.; Helm, L.; Borel, A.; Daul, C. A. Comptes Rendus Chimie 2012, 15 (2-3), 250–254. Sherry, A. D.; Caravan, P.; Lenkinski, R. E. Journal of Magnetic Resonance Imaging 2009, 30 (6), 1240–1248. Takahashi, M.; Tsutsui, H.; Murayama, C.; Miyazawa, T.; Fritz-Zieroth, B. Magnetic Resonance Imaging 1996, 14 (6), 619–623. Zhou, Z.; Lu, Z.-R. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 2013, 5 (2), 190–190.