DOTA (1,4,7,10-tetraazacyclododecane-N,N’,N”,N”’-tetraacetic acid) forms chelates with metals, which has been widely applied in production of radioligands for SPECT, MRI, and PET. DTPA (diethylene triamine pentaacetic acid) has similar properties. Usually, DOTA and DTPA are used to link metal ion to a peptide or other large organic molecule with specificity to a certain receptor or metabolic process.
Gadolinium ion (Gd3+) chelates (Gd-DOTA and Gd-DTPA) have been used as a contrast agent in MRI, for example to measure myocardial perfusion (Larsson et al., 2001; Pärkkä et al., 2006), viability (Pereira et al., 2001), extracellular volume (Banypersad et al., 2013); perfusion and extracellular volume in rheumatoid arthritis (Hodgson et al., 2007); and cerebral perfusion and blood-brain barrier (BBB) permeability (Tofts, 1996; Nagaraja et al., 2011; Kellner et al., 2014). Gd-DOTA shows rapid and passive extravascular diffusion in the interstitial space without intracellular penetration, followed by a rapid urinary excretion via glomerular filtration (Le Mignon et al., 1990). Gd-DOTA does not cross the blood brain barrier in the healthy brain tissue.
It is plausible that gallium ion (Ga3+) labeled DOTA acts similarly in the body. [67Ga]DTPA has been used to measure passive BBB permeability in rat autoradiography studies (Uehara et al., 1997; Miyagawa et al., 1998, 2003). [64Cu]DOTA could be used to assess myocardial extracellular volume and fibrosis (Kim et al., 2016).
NODAGA and HBED-CC are alternative bifunctional chelating agents for 68Ga3+. NODAGA has faster labelling kinetics, and 68Ga3+ labelling is possible in room temperature (Kumar et al., 2018).
[68Ga]DOTA as perfusion tracer
Autio et al (2014) have used [68Ga]DOTA as a perfusion tracer in dynamic PET studies of rats. Studies were analyzed using one-tissue compartmental model, similar to the compartmental model for radiowater. The estimated K1 was at the same level as blood flow measured using radiowater in inflamed and normal tissue. Blood flow and [68Ga]DOTA K1 were clearly higher in inflamed tissue than in normal tissue. K1/k2 ratio may be another parameter of interest since it represents the extracellular volume, and vascular permeability in the brain.
[68Ga]DOTA could also be used to measure pulmonary blood flow (Velasco et al., 2017).
Autio A, Saraste A, Kudomi N, Saanijoki T, Johansson J, Liljenbäck H, Tarkia M, Oikonen V, Sipilä HT, Roivainen A. Assessment of blood flow with 68Ga-DOTA PET in experimental inflammation: a validation study using 15O-water. Am J Nucl Med Mol Imaging 2014; 4(6): 571-579.
Autio A, Liljenbäck H, Saraste A, Oikonen V, Tarkia M, Kudomi N, Saanijoki T, Sipilä H, Johansson J, Roivainen A. 15O-Water and 68Ga-DOTA PET imaging for assessment of blood flow and vascular permeability in a rat model of inflammation - comparison with ultrasound imaging. Abstracts of the 2011 World Molecular Imaging Congress, P680.
Banypersad SM, Sado DM, Flett AS, Gibbs SD, Pinney JH, Maestrini V, Cox AT, Fontana M, Whelan CJ, Wechalekar AD, Hawkins PN, Moon JC. Quantification of myocardial extracellular volume fraction in systemic AL amyloidosis: an equilibrium contrast cardiovascular magnetic resonance study. Circ Cardiovasc Imaging 2013 Jan 1;6(1):34-39.
Hodgson RJ, Connolly S, Barnes T, Eyes B, Campbell RSD, Moots R. Pharmacokinetic modeling of dynamic contrast-enhanced MRI of the hand and wrist in rheumatoid arthritis and the response to anti-tumor necrosis factor-α therapy. Magn Reson Med. 2007; 58: 482-489.
Kellner E, Mix M, Reisert M, Förster K, Nguyen-Thanh T, Splitthoff DN, Gall P, Kiselev VG, Mader I. Quantitative cerebral blood flow with bolus tracking perfusion MRI: Measurements in porcine model and comparison with H215O PET. Magn Reson Med. 2014; 72(6): 1723-1734.
Larsson HBW, Rosenbaum S, Fritz-Hansen T. Quantification of the effect of water exchange in dynamic contrast MRI perfusion measurements in the brain and heart. Magn Reson Med. 2001; 46: 272-281.
Le Mignon MM, Chambon C, Warrington S, Davies R, Bonnemain B. Gd-DOTA. Pharmacokinetics and tolerability after intravenous injection into healthy volunteers. Invest Radiol. 1990; 25(8): 933-937.
Miyagawa T, Oku T, Uehara H, Desai R, Beattie B, Tjuvajev J, Blasberg R. “Facilitated” amino acid transport is upregulated in brain tumors. J Cereb Blood Flow Metab. 1998; 18(5): 500-509.
Miyagawa T, Oku T, Sasajima T, Dasai R, Beattie B, Finn R, Tjuvajev JG, Blasberg R. Assessment of treatment response by autoradiography with 14C-aminocyclopentane carboxylic acid, 67Ga-DTPA, and 18F-FDG in a herpes simplex virus thymidine kinase/ganciclovir brain tumor model. J Nucl Med. 2003; 44(11): 1845-1854.
Nagaraja TN, Ewing JR, Karki K, Jacobs PE, Divine GW, Fenstermacher JD, Patlak CS, Knight RA. MRI and quantitative autoradiographic studies following bolus injections of unlabeled and 14C-labeled gadolinium-diethylenetriaminepentaacetic acid in a rat model of stroke yield similar distribution volumes and blood-to-brain influx rate constants. NMR Biomed. 2011;24(5): 547-558.
Pereira RS, Prato FS, Wisenberg G, Sykes J, Yvorchuk KJ. The use of Gd-DTPA as a marker of myocardial viability in reperfused acute myocardial infarction. Int J Cardiovasc Imaging 2001; 17: 395-404.
Pärkkä JP, Niemi P, Saraste A, Koskenvuo JW, Komu M, Oikonen V, Toikka JO, Kiviniemi TO, Knuuti J, Sakuma H, Hartiala JJ. Comparison of MRI and positron emission tomography in measuring myocardial perfusion reserve in healthy humans. Magn Reson Med. 2006; 55(4): 772-779.
Tofts PS. Optimal detection of blood-brain barrier defects with Gd-DTPA MRI - the influences of delayed imaging and optimised repetition time. Magn Reson Imaging 1996; 14(4): 373-380.
Uehara H, Miyagawa T, Tjuvajev J, Joshi R, Beattie B, Oku T, Finn R, Blasberg R. Imaging experimental brain tumors with 1-aminocyclopentane carboxylic acid and alpha-aminoisobutyric acid: comparison to fluorodeoxyglucose and diethylenetriaminepentaacetic acid in morphologically defined tumor regions. J Cereb Blood Flow Metab. 1997; 17(11): 1239-1253.
Wieseotte C, Wagner M, Schreiber LM. An estimate of Gd-DOTA diffusivity in blood by direct NMR diffusion measurement of its hydrodynamic analogue Ga-DOTA. Poster presentation in Joint Annual Meeting ISMRM-ESMRMB 2014.
Updated at: 2018-09-26
Created at: 2014-12-19
Written by: Vesa Oikonen