Kap 11 MR kontrastmidler. MR Contrast Agents (MRCA) 5/1/2011 FYS-KJM MR Contrast Agents on the market or in clinical development*

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1 FYS-KJM 4740 Magnetic properties Biodistribution Image enhancement MR-teori og medisinsk diagnostikk Kap 11 MR kontrastmidler Paramagnetic Superparamagnetic Extracellular fluid (ECF) Intravascular (blood pool) Tissue specific Positive (predominant T1-shortening) Negative (predominant T2- shortening) MR Contrast Agents on the market or in clinical development* Short Name Generic Name Trade Name Enhancement Pattern (primary) MR Contrast Agents (MRCA) ECF agents: GdDTPA gadopentetate dimeglumine GdDTA gadoterate meglumine GdDTPA-BMA gadodiamide injection GdHP-D3A gadoterol injection GdDTPA-BMEA gadoversetamide GdD3A-butriol gadobutrol GdBPTA/Dimeg gadobenate dimeglumine rgan specific agents: MnDPDP mangafodipir trisodium GdEB-DTPA gadoxetic acid GdBPTA/Dimeg gadobenate dimeglumine AMI-25 ferumoxides (SPI) SHU 555A* ferrixan (SPI) AMI-227 # Ferumoxtran SHU 555 C* # Ferucarotran Magnevist Dotarem mniscan ProHance ptimark Gadovist MutliHance Teslascan Eovist MultiHance Endorem/Feridex Resovist Sinerem/Combidex negative negative negative Positive/negative A contrast agent is nothing more than a catalyst that decreases the T 1 and/or T 2 of the tissue protons T 1 and T 2 relaxation are NT independent processes T 1 cannot be reduced without reducing T 2 T 2 can be reduced without reducing T 1 Blood pool agents: MS-325 gadomer-17 P792 Angiomark * adapted from Rinck et al. Magnetic Resonance in Medicine (2001) # = also blood pool agents MRCA effectiveness (ability to alter 1/T 1 and 1/T 2 ) in vitro - in a homogeneous medium - is a linear function of [CA]: 1/T 1,2 Contrast Agent Relaxivity in vitro [CA] (mm) Contrast Agent Relaxivity in vitro In vitro MRCA relaxivity, r 1 and r 2 : 1 T 1,2 = r 1,2 1 [ CA] + T r 1 = T 1 relaxivity; r 2 =T 2 relaxivity r 1,2 is due to dipolar (short range) interactions r 1,2 must be specified at a given temp, field stregth and medium 1,2 pre Commonly use relaxation rate (1/T 1,2 ) due to linear relationship with [CA] 1

2 Contrast agents - basic principles Two types of magnetic effects are used clinically to induce T 2 - and T 1 -shortening: Paramagnetism Superparamagnetism Paramagnetic ions Metal ions with unpaired electrons: gadolinium (Gd 3+ ) iron (Fe 2+ /Fe 3+ ) manganese (Mn 2+) Gd 3 + Magnetic moment of unpaired electrons is >> magnetic moment of protons Dipolar magnetic interaction between electrons and water protons Metal chelate use of biocompatible ligand Paramagnetic chelates enhance contrast in T1-w images H H CH N 3 H Tissue signal Tumour post-gd N H 3C H Gd N N N Pre-Gd contrast Post-Gd contrast Tumour pre-gd Brain TR Paramagnetic ions Typical in vitro relaxivity of small MW gadolinium chelates : r 1 4 mm -1 s -1 r mm -1 s -1 Relaxivity is limited by rapid tumbling rate of the Gdchelate T 1 relaxivity can be increased by selective binding to macromolecules (proteins) or by combinding multiple Gdions in a rigid structure (polymers) Will also modify biodistribution from extracellular to intravascular. Superparamagnetic Iron xide Particles; Iron oxide particles (nanoparticles) made up of several thousand magnetic ions in the form of magnetite or maghemite crystals Much larger magnetic moment than paramagnetic agents Developed as liver/spleen/lymph node specific (T 2 ) or blood pool (T 1,T 2 ) agents Imaging effect and biodistribution is size dependent Typical in vitro relaxivity of iron oxide nanoparticles : r 1 20 mm -1 s -1 r 2 40 mm -1 s -1 2

3 Iron oxides have much larger magnetic moment than gadolinium and are therefore much more potent relaxation enhancers Dipolar relaxivity is a complex function of CA properties Important dependence of effective correlation rate of molecule: 1/T 1m and 1/T 2m dependent on spectral density functions of the form: In vivo CA effects Water exchange effects e.g. spin echo sequence: Rel SI /τ=k 1 + k CA concentration (mm) Fast exchange: Slow exchange: Water exchange influence T1-relaxation: Bloch equations including water exchange terms: Mono-exp approximation: 3

4 k i =proton exchange rate (i.v. -> e.c.) 1/T1 t Permeability-surface area (PS) product: PS=k i *BV Initial slope: BV (=i.v. blood volume) 1/T1 b Results: renal cortex Results: myocardium PS prod: 62 +/- 3 ml/g/min BV : 19 +/- 1.5 ml/100 g PS prod: 9.4 +/- 3.7 ml/g/min BV : /- 2 ml/100 g Bjørnerud et al. MRM 2001 Bjørnerud et al. MRM 2002 Parametric water exchange maps Summary in vivo T1-effects of CA ml/100 g ml/g/min BV map 0 PS map 0 4

5 Susceptibility induced relaxation: M z =χh 0 (H=B o /µ 0 ). Iron oxides have much larger magnetic moment than gadolinium and are therefore much more potent relaxation enhancers Langevin equation: For paramagnetic agents, Curie law approximation valid < 50 T Susceptibility constant Microscopic field inhomogeneities due to intravascular CA Susceptibility induced relaxation Diamagnetic blood + CA M i >> M e Bo P(ω) Gaussian or Lorentzian Lorentzian lineshape Gaussian lineshape Effective 1/T2* is proportional to linewidth of spectrum => monoexponential signal decay Effective 1/T2* is proportional to σ 2 TE : i.e. measured T2* is function of TE. 5

6 Advanced Applications of MR Contrast Agents Summary susceptibility induced relaxation General requirement: estimate contrast agent concentration in vivo (at least to within a scaling constant) T 1 -based dynamic imaging Most accurate approach: quantification of 1/T 1 Then, assuming fast water exchange: C(t)=k R 1 (t) Estimation of C(t) from T1-GRE sequence: Requirement: TR<<T1 and TE<<T2* then: T2/T2* based dynamic imaging Assumption: monoexponential T2/T2* signal decay (Lorentzian lineshape) Then: If T1-effects are negligible then: DSC dynamic signal change T2/T2* based dynamic imaging Raw data t=0 SI 0 SI baseline first pass Steady-state time Re-circulation R 2 * maps 5/1/2011 time 35 raw data 6

7 Perfusion imaging Central volume principle: Blood volume maps in tumor imaging: C a (t) C t (t) * k SI( t) R = = 2 ( t) k C( t) loge TE SI0 rcbv R2( t) dt V t F a MTT Measurement of flow (perfusion) and MTT: C a (t) Perfusjons-MR Introducing the tissue residue function R(t) arterie Vevets residualfunksjon C(t) R(t) kapillærnett vene Standard dekonvolusjonsproblem MR perfusjonsavbilding MTT = V/F C a (t) BV BF MTT C(t) F R(t) 7

8 Slag: Forlenget MTT = area at risk 3 timer efter slag Dynamic contrast enhanced imaging Two-compartment model: K trans Plasma EES k ep T2 DWI Østergaard et al, Århus, Danmark rmtt 5 dagers oppfølging med DWI K trans and K ep related to leakiness of capillary wall Dynamic contrast enhanced imaging Two-compartment model: Dynamic contrast enhanced imaging If not, need to assume C p (t) to be monoexponential Transfer constants can be determined if C(t) can be measured in tissue and artery (AIF) Dynamic contrast enhanced imaging