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+) labelled 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 and 2020) have used [68Ga]DOTA as a perfusion tracer in dynamic PET studies of rats. Studies were analysed 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 non-inflamed tissue. Blood flow and [68Ga]DOTA K1 were clearly higher in inflamed tissue than in normal tissue (Autio et al., 2014). In rat model of myocardial infarction, K1 was lower than in normal myocardium, and correlated well with perfusion obtained with [1-11C]acetate. After 10 min, [68Ga]DOTA uptake was higher in infarcted than in normal myocardium. Both K1 and late retention can be used to detect myocardial infarction (Autio et al., 2020). Velasco et al (2020) validated [68Ga]DOTA method for myocardial perfusion assessment in pig model of myocardial infarction against microspheres method. In this large animal model the spillover effects from right and left cavities could be included in the analysis method, and extraction fraction of [68Ga]DOTA could be estimated. K1/k2 ratio, representing extracellular volume, was increased in infarcted area (Velasco et al., 2020).
[68Ga]DOTA could also be used to measure pulmonary blood flow; Velasco et al (2017) validated the method in pigs against microspheres method. Input function was derived from the image by placing ROI on right ventricular cavity, and model included three fitted parameters, flow, PS, and plasma volume (Velasco et al., 2017).
Other applications of [68Ga]DOTA
K1/k2 represents the extracellular volume in peripheral organs, and could be used as an index of vascular permeability (status of BBB) in the brain.
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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.
Autio A, Uotila S, Kiugel M, Kytö V, Liljenbäck H, Kudomi N, Oikonen V, Metsälä O, Helin S, Knuuti J, Saraste A, Roivainen A. 68Ga-DOTA chelate, a novel imaging agent for assessment of myocardial perfusion and infarction detection in a rodent model. J Nucl Cardiol. 2020; 27(3): 891-898. doi: 10.1007/s12350-019-01752-6.
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. doi: 10.1002/mrm.25073.
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. PMID: 2394577.
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. doi: 10.1002/mrm.20833.
Velasco C, Mota-Cobián A, Mota RA, Pellico J, Herranz F, Galán-Arriola C, Ibáñez B, Ruiz-Cabello J, Mateo J, España S. Quantitative assessment of myocardial blood flow and extracellular volume fraction using 68Ga-DOTA-PET: A feasibility and validation study in large animals. J Nucl Cardiol. 2020; 27(4): 1249-1260. doi: 10.1007/s12350-019-01694-z.
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: 2019-05-04
Created at: 2014-12-19
Written by: Vesa Oikonen