Quantification [18F]DPA-714 PET studies
DPA-714 (and previous molecule DPA-713) is a selective ligand for the translocator protein (TSPO), formerly known as peripheral benzodiazepine receptor (PBR).
James et al. (2008) performed [18F]DPA-714 PET studies with rats and a baboon (P. hamadryas). Studies have shown rapid brain uptake, good retention, and effective displacement (James et al., 2008). Spinal cord has been studied in rats (Abourbeh et al., 2012) and mice (Gargiulo et al., 2016).
Chauveau et al. (2009) compared F-18 labelled DPA-714 to C-11 labelled DPA-713 and to the classical (but not optimal) TSPO tracer [11C]-(R)-PK11195 in a rat model of acute neuroinflammation, and found that the highest binding potential (BP) and ipsilaterial-to-contralateral ratio were achieved with [18F]DPA-714. Displacement studies provided additional support for the usefulness of this tracer.
Lavisse et al. (2015a) studied cynomolgus monkeys, healthy and with induced neurodegeneration. Results also support the usefulness of [18F]DPA-714. Saba et al. (2017) studied baboons, and noticed increased binding after acute alcohol exposure.
Longitudinal [18F]DPA-714 PET imaging in transgenic mouse model of Alzheimer’s disease could demonstrate increased neuroinflammation (Takkinen et al., 2017). In a mouse model of focal TBI [18F]DPA-714 has shown chronic neuroinflammation in regions remote from the initial site of injury (Hosomi et al., 2018).
[18F]DPA-714 and related radioligands contain the 18F on terminal position of an alkoxy chain, bonded to an aromatic moiety through oxygen atom, which has been shown to lead to appearance of radiometabolites in the plasma (Peyronneau et al., 2013). Radiometabolite formation could be reduced by attaching 18F directly to the aromatic ring (Keller et al., 2018).
In rats and baboons, [18F]DPA-714 is rapidly metabolized into at least three radiometabolites that are less lipophilic than the native radioligand (Peyronneau et al., 2013). Carboxylic acid derivative represents 15% of rat brain uptake 2 h after administration, but uptake is not specific and less than concentration in the plasma (Peyronneau et al., 2013). Chauveau et al. (2009) could detect only native radioligand in the brain 60 min after injection, and one radiometabolite in the plasma. Parent tracer fractions were 75%, 63% and 14% at 20, 40 and 60 min after injection (Chauveau et al., 2009). Similar results were obtained with [11C]DPA-713 (Boutin et al., 2007). In baboons the initial metabolism seems to be faster, with native tracer fractions of about 60% and 40% at 20 and 40 min (Peyronneau et al., 2013), but at 60 min the native tracer fraction is 30-40%, higher than in rats (Peyronneau et al., 2013; Saba et al., 2017).
Published analysis methods
Chauveau et al. (2009) analysed [18F]DPA-714 rat brain studies with SRTM, using contralateral ROI as reference input curve. PET scan duration was 70 min. BP was 3.08 ± 0.67. R1 was higher (1.64 ± 0.27) than with [11C]PK11195 (1.10 ± 0.06) or [11C]DPA-713 (1.30 ± 0.27). Wang et al. (2014) calculated simple lesion-to-normal ratio in rat brain injury model, and confirmed the result with displacement. SUV ratios have been used to analyse mouse studies (Gargiulo et al., 2016; Hosomi et al., 2019). Pottier et al (2014) quantified [18F]DPA-714 uptake as simple %ID/cc values at 45-60 min p.i. in a rat model of rheumatoid arthritis.
For human studies it is necessary to do genotyping for high, mixed, and low affinity binders (HAB, MAB, and LAB, respectively), and LABs (about 11% of population) should be excluded from PET studies with [18F]DPA-714. Human brain data have been quantified using reversible 2-tissue compartmental model, Logan plot, and simplified reference tissue model using cerebellar grey matter as reference tissue (Golla et al., 2015 and 2016; Lavisse et al., 2015b). SRTM2 and Logan plot with reference input can provide accurate BPND images (Golla et al., 2016).
Suggested analysis method for Turku
Calculation of VT using Logan plot or reversible two-tissue compartmental model is recommended, if arterial input can be measured. If arterial input is not available, SUV can be used, or SUV ratio and simplified reference tissue model, if reference tissue is not affected by the studied disease or medication.
In human studies the different binding groups must be analysed separately, with own control groups. SRTM or Logan plot with reference input can be used for computing parametric BPND images.
Awde AR, Boisgard R, Thézé B, Dubois A, Zheng J, Dollé F, Jacobs AH, Tavitian B, Winkeler A. The translocator protein radioligand 18F-DPA-714 monitors antitumor effect of erufosine in a rat 9L intracranial glioma model. J Nucl Med. 2013; 54(12): 2125-2131.
Boutin H, Chauveau F, Thominiaux C, Grégoire M-C, James ML, Trebossen R, Hantraye P, Dollé F, Tavitian B, Kassiou M. 11C-DPA-713: A novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation. J Nucl Med. 2007; 48: 573-581.
Boutin H, Prenant C, Maroy R, Galea J, Greenhalgh AD, Smigova A, Cawthorne C, Julyan P, Wilkinson SM, Banister SD, Brown G, Herholz K, Kassiou M, Rothwell NJ. [18F]DPA-714: direct comparison with [11C]PK11195 in a model of cerebral ischemia in rats. PLoS One 2013; 8(2): e56441. doi: 10.1371/journal.pone.0056441.
Chauveau F, Van Camp N, Dollé F, Kuhnast B, Hinnen F, Damont A, Boutin H, James M, Kassiou M, Tavitian B. Comparative evaluation of the translocator protein radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a rat model of acute neuroinflammation. J Nucl Med. 2009; 50(3): 468-476. doi: 10.2967/jnumed.108.058669.
Doorduin J, Klein HC, Dierckx RA, James M, Kassiou M, de Vries EFJ. [11C]-DPA-713 and [18F]-DPA-714 as new PET tracers for TSPO: a comparison with [11C]-(R)-PK11195 in a rat model of Herpes Encephalitis. Mol Imaging Biol. 2009; 11: 386-398. doi: 10.1007/s11307-009-0211-6.
Gent YY, Weijers K, Molthoff CF, Windhorst AD, Huisman MC, Kassiou M, Jansen G, Lammertsma AA, van der Laken CJ. Promising potential of new generation translocator protein tracers providing enhanced contrast of arthritis imaging by positron emission tomography in a rat model of arthritis. Arthritis Res Ther. 2014; 16(2): R70. doi: 10.1186/ar4509.
Golla SS, Boellaard R, Oikonen V, Hoffmann A, van Berckel BN, Windhorst AD, Virta J, Haaparanta-Solin M, Luoto P, Savisto N, Solin O, Valencia R, Thiele A, Eriksson J, Schuit RC, Lammertsma AA, Rinne JO. Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer’s disease patients. J Cereb Blood Flow Metab. 2015; 35(5): 766-772. doi: 10.1038/jcbfm.2014.261.
Golla SSV, Boellaard R, Oikonen V, Hoffmann A, van Berckel BNM, Windhorst AD, Virta J, te Beek ET, Groeneveld GJ, Haaparanta-Solin M, Luoto P, Savisto N, Solin O, Valencia R, Thiele A, Eriksson J, Schuit RC, Lammertsma AA, Rinne JO. Parametric binding images of the TSPO ligand 18F-DPA-714. J Nucl Med. 2016; 57: 1543-1547. doi: 10.2967/jnumed.116.173013.
James ML, Fulton RR, Vercoullie DJ, Henderson DJ, Garreau L, Chalon S, Dolle F, Costa B, Guilloteau D, Kassiou M. DPA-714, a new translocator protein-specific ligand: synthesis, radiofluorination, and pharmacologic characterization. J Nucl Med. 2008; 49: 814-822. doi: 10.2967/jnumed.107.046151.
Lavisse S, Inoue K, Jan C, Peyronneau MA, Petit F, Goutal S, Dauguet J, Guillermier M, Dollé F, Rbah-Vidal L, Van Camp N, Aron-Badin R, Remy P, Hantraye P. [18F]DPA-714 PET imaging of translocator protein TSPO (18 kDa) in the normal and excitotoxically-lesioned nonhuman primate brain. Eur J Nucl Med Mol Imaging 2015a; 42(3): 478-494. doi: 10.1007/s00259-014-2962-9.
Lavisse S, García-Lorenzo D, Peyronneau MA, Bodini B, Thiriez C, Kuhnast B, Comtat C, Remy P, Stankoff B, Bottlaender M. Optimized quantification of translocator protein radioligand 18F-DPA-714 uptake in the brain of genotyped healthy volunteers. J Nucl Med. 2015b; 56(7): 1048-1054. doi: 10.2967/jnumed.115.156083.
Martín A, Boisgard R, Thézé B, Van Camp N, Kuhnast B, Damont A, Kassiou M, Dollé F, Tavitian B. Evaluation of the PBR/TSPO radioligand [18F]DPA-714 in a rat model of focal cerebral ischemia. J Cereb Blood Flow Metab. 2010; 30(1): 230-241. doi: 10.1038/jcbfm.2009.205.
Martín A, Boisgard R, Kassiou M, Dollé F, Tavitian B. Reduced PBR/TSPO expression after minocycline treatment in a rat model of focal cerebral ischemia: a PET study using [18F]DPA-714. Mol Imaging Biol. 2011; 13(1): 10-15. doi: 10.1007/s11307-010-0324-y.
Peyronneau MA, Saba W, Goutal S, Damont A, Dollé F, Kassiou M, Bottlaender M, Valette H. Metabolism and quantification of [18F]DPA-714, a new TSPO positron emission tomography radioligand. Drug Metab Dispos. 2013; 41(1): 122-131. doi: 10.1124/dmd.112.046342.
Wang Y, Yue X, Kiesewetter DO, Niu G, Teng G, Chen X. PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714. Eur J Nucl Med Mol Imaging 2014; 41: 1440-1449. doi: 10.1007/s00259-014-2727-5.
Winkeler A, Boisgard R, Awde AR, Dubois A, Thézé B, Zheng J, Ciobanu L, Dollé F, Viel T, Jacobs AH, Tavitian B. The translocator protein ligand [18F]DPA-714 images glioma and activated microglia in vivo. Eur J Nucl Med Mol Imaging. 2012; 39(5): 811-823. doi: 10.1007/s00259-011-2041-4.
Wu C, Yue X, Lang L, Kiesewetter DO, Li F, Zhu Z, Niu G, Chen X. Longitudinal PET imaging of muscular inflammation using 18F-DPA-714 and 18F-Alfatide II and differentiation with tumors. Theranostics 2014; 4(5): 546-555. doi: 10.7150/thno.8159.
Updated at: 2019-02-13
Created at: 2009-02-27
Written by: Vesa Oikonen