Top

European Journal of Nuclear Medicine and Molecular Imaging

Published in:

01-02-2015 | Original Article

Targeting post-infarct inflammation by PET imaging: comparison of ⁶⁸Ga-citrate and ⁶⁸Ga-DOTATATE with ¹⁸F-FDG in a mouse model

Authors: James T. Thackeray, Jens P. Bankstahl, Yong Wang, Mortimer Korf-Klingebiel, Almut Walte, Alexander Wittneben, Kai C. Wollert, Frank M. Bengel

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 2/2015

Abstract

ᅟ

Imaging of inflammation early after myocardial infarction (MI) is a promising approach to the guidance of novel molecular interventions that support endogenous healing processes. ¹⁸F-FDG PET has been used, but may be complicated by physiological myocyte uptake. We evaluated the potential of two alternative imaging targets: lactoferrin binding by ⁶⁸Ga-citrate and somatostatin receptor binding by ⁶⁸Ga-DOTATATE.

Methods

C57Bl/6 mice underwent permanent coronary artery ligation. Serial PET imaging was performed 3 – 7 days after MI using ⁶⁸Ga-citrate, ⁶⁸Ga-DOTATATE, or ¹⁸F-FDG with ketamine/xylazine suppression of myocyte glucose uptake. Myocardial perfusion was evaluated by ¹³N-ammonia PET and cardiac geometry by contrast-enhanced ECG-gated CT.

Results

Mice exhibited a perfusion defect of 30 – 40 % (of the total left ventricle) with apical anterolateral wall akinesia and thinning on day 7 after MI. ¹⁸F-FDG with ketamine/xylazine suppression demonstrated distinct uptake in the infarct region, as well as in the border zone and remote myocardium. The myocardial standardized uptake value in MI mice was significantly higher than in healthy mice under ketamine/xylazine anaesthesia (1.9 ± 0.4 vs. 1.0 ± 0.1). ⁶⁸Ga images exhibited high blood pool activity with no specific myocardial uptake up to 90 min after injection (tissue-to-blood contrast 0.9). ⁶⁸Ga-DOTATATE was rapidly cleared from the blood, but myocardial SUV was very low (0.10 ± 0.03).

Conclusion

Neither ⁶⁸Ga nor ⁶⁸Ga-DOTATATE is a useful alternative to ¹⁸F-FDG for PET imaging of myocardial inflammation after MI in mice. Among the three tested approaches, ¹⁸F-FDG with ketamine/xylazine suppression of cardiomyocyte uptake remains the most practical imaging marker of post-infarct inflammation.

Available only for authorised users

Mezzaroma E, Toldo S, Farkas D, Seropian IM, Van Tassell BW, Salloum FN, et al. The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc Natl Acad Sci U S A. 2011;108:19725–30. doi:10.1073/pnas.1108586108.PubMedCentralPubMedCrossRef

Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013;339:161–6. doi:10.1126/science.1230719.PubMedCentralPubMedCrossRef

Kempf T, Zarbock A, Vestweber D, Wollert KC. Anti-inflammatory mechanisms and therapeutic opportunities in myocardial infarct healing. J Mol Med. 2012;90:361–9. doi:10.1007/s00109-011-0847-y.PubMedCrossRef

Bengel FM, George RT, Schuleri KH, Lardo AC, Wollert KC. Image-guided therapies for myocardial repair: concepts and practical implementation. Eur Heart J Cardiovasc Imaging. 2013;14:741–51. doi:10.1093/ehjci/jet038.PubMedCentralPubMedCrossRef

Basu S, Zhuang H, Torigian DA, Rosenbaum J, Chen W, Alavi A. Functional imaging of inflammatory diseases using nuclear medicine techniques. Semin Nucl Med. 2009;39:124–45. doi:10.1053/j.semnuclmed.2008.10.006.PubMedCrossRef

Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, et al. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation. 2002;105:2708–11.PubMedCrossRef

Lee WW, Marinelli B, van der Laan AM, Sena BF, Gorbatov R, Leuschner F, et al. PET/MRI of inflammation in myocardial infarction. J Am Coll Cardiol. 2012;59:153–63. doi:10.1016/j.jacc.2011.08.066.PubMedCentralPubMedCrossRef

Campian ME, Hardziyenka M, de Bruin K, van Eck-Smit BL, de Bakker JM, Verberne HJ, et al. Early inflammatory response during the development of right ventricular heart failure in a rat model. Eur J Heart Fail. 2010;12:653–8. doi:10.1093/eurjhf/hfq066.PubMedCrossRef

Campian ME, Verberne HJ, Hardziyenka M, de Groot EA, van Moerkerken AF, van Eck-Smit BL, et al. Assessment of inflammation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Eur J Nucl Med Mol Imaging. 2010;37:2079–85. doi:10.1007/s00259-010-1525-y.PubMedCentralPubMedCrossRef

10.

Chen WC, Tsai KD, Chen CH, Lin MS, Chen CM, Shih CM, et al. Role of gallium-67 scintigraphy in the evaluation of occult sepsis in the medical ICU. Intern Emerg Med. 2012;7:53–8. doi:10.1007/s11739-011-0739-8.PubMedCrossRef

11.

Hofman MS, Kong G, Neels OC, Eu P, Hong E, Hicks RJ. High management impact of Ga-68 DOTATATE (GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours. J Med Imaging Radiat Oncol. 2012;56:40–7. doi:10.1111/j.1754-9485.2011.02327.x.PubMedCrossRef

12.

Silvola JM, Laitinen I, Sipila HJ, Laine VJ, Leppanen P, Yla-Herttuala S, et al. Uptake of 68gallium in atherosclerotic plaques in LDLR-/-ApoB100/100 mice. EJNMMI Res. 2011;1:14. doi:10.1186/2191-219X-1-14.PubMedCentralPubMedCrossRef

13.

Kayani I, Conry BG, Groves AM, Win T, Dickson J, Caplin M, et al. A comparison of 68Ga-DOTATATE and 18F-FDG PET/CT in pulmonary neuroendocrine tumors. J Nucl Med. 2009;50:1927–32. doi:10.2967/jnumed.109.066639.PubMedCrossRef

14.

Armani C, Catalani E, Balbarini A, Bagnoli P, Cervia D. Expression, pharmacology, and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages. J Leukoc Biol. 2007;81:845–55. doi:10.1189/jlb.0606417.PubMedCrossRef

15.

Schatka I, Wollenweber T, Haense C, Brunz F, Gratz KF, Bengel FM. Peptide receptor targeted radionuclide therapy alters inflammation in atherosclerotic plaques. J Am Coll Cardiol. 2013;62:2344–5. doi:10.1016/j.jacc.2013.08.1624.PubMedCrossRef

16.

Kempf T, Zarbock A, Widera C, Butz S, Stadtmann A, Rossaint J, et al. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med. 2011;17:581–8. doi:10.1038/nm.2354.PubMedCrossRef

17.

Korf-Klingebiel M, Kempf T, Schluter KD, Willenbockel C, Brod T, Heineke J, et al. Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction. Circulation. 2011;123:504–14. doi:10.1161/CIRCULATIONAHA.110.989665.PubMedCrossRef

18.

White DA, Su Y, Kanellakis P, Kiriazis H, Morand EF, Bucala R, et al. Differential roles of cardiac and leukocyte derived macrophage migration inhibitory factor in inflammatory responses and cardiac remodelling post myocardial infarction. J Mol Cell Cardiol. 2014;69:32–42. doi:10.1016/j.yjmcc.2014.01.015.PubMedCrossRef

19.

Guo N, Lang L, Li W, Kiesewetter DO, Gao H, Niu G, et al. Quantitative analysis and comparison study of [18F]AlF-NOTA-PRGD2, [18F]FPPRGD2 and [68Ga]Ga-NOTA-PRGD2 using a reference tissue model. PLoS One. 2012;7:e37506. doi:10.1371/journal.pone.0037506.PubMedCentralPubMedCrossRef

20.

Perez J, Viollet C, Doublier S, Videau C, Epelbaum J, Baud L. Somatostatin binds to murine macrophages through two distinct subsets of receptors. J Neuroimmunol. 2003;138:38–44.PubMedCrossRef

21.

Li X, Samnick S, Lapa C, Israel I, Buck AK, Kreissl MC, et al. 68Ga-DOTATATE PET/CT for the detection of inflammation of large arteries: correlation with 18F-FDG, calcium burden and risk factors. EJNMMI Res. 2012;2:52. doi:10.1186/2191-219X-2-52.PubMedCentralPubMedCrossRef

22.

Rominger A, Saam T, Vogl E, Ubleis C, la Fougere C, Forster S, et al. In vivo imaging of macrophage activity in the coronary arteries using 68Ga-DOTATATE PET/CT: correlation with coronary calcium burden and risk factors. J Nucl Med. 2010;51:193–7. doi:10.2967/jnumed.109.070672.PubMedCrossRef

23.

Cotugno G, Aurilio M, Annunziata P, Capalbo A, Faella A, Rinaldi V, et al. Noninvasive repetitive imaging of somatostatin receptor 2 gene transfer with positron emission tomography. Hum Gene Ther. 2011;22:189–96. doi:10.1089/hum.2010.098.PubMedCentralPubMedCrossRef

24.

Saha JK, Xia J, Grondin JM, Engle SK, Jakubowski JA. Acute hyperglycemia induced by ketamine/xylazine anesthesia in rats: mechanisms and implications for preclinical models. Exp Biol Med (Maywood). 2005;230:777–84.

25.

Ahmed N, Kansara M, Berridge MV. Acute regulation of glucose transport in a monocyte-macrophage cell line: Glut-3 affinity for glucose is enhanced during the respiratory burst. Biochem J. 1997;327(Pt 2):369–75.PubMedCentralPubMed

26.

Lumeng CN, Deyoung SM, Saltiel AR. Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins. Am J Physiol Endocrinol Metab. 2007;292:E166–74. doi:10.1152/ajpendo.00284.2006.PubMedCentralPubMedCrossRef

27.

Cheng VY, Slomka PJ, Le Meunier L, Tamarappoo BK, Nakazato R, Dey D, et al. Coronary arterial 18F-FDG uptake by fusion of PET and coronary CT angiography at sites of percutaneous stenting for acute myocardial infarction and stable coronary artery disease. J Nucl Med. 2012;53:575–83. doi:10.2967/jnumed.111.097550.PubMedCrossRef

28.

Harisankar CN, Mittal BR, Agrawal KL, Abrar ML, Bhattacharya A. Utility of high fat and low carbohydrate diet in suppressing myocardial FDG uptake. J Nucl Cardiol. 2011;18:926–36. doi:10.1007/s12350-011-9422-8.PubMedCrossRef

29.

Roivainen A, Jalkanen S, Nanni C. Gallium-labelled peptides for imaging of inflammation. Eur J Nucl Med Mol Imaging. 2012;39 Suppl 1:S68–77. doi:10.1007/s00259-011-1987-6.PubMedCrossRef

30.

Saraste A, Laitinen I, Weidl E, Wildgruber M, Weber AW, Nekolla SG, et al. Diet intervention reduces uptake of alphavbeta3 integrin-targeted PET tracer 18F-galacto-RGD in mouse atherosclerotic plaques. J Nucl Cardiol. 2012;19:775–84. doi:10.1007/s12350-012-9554-5.PubMedCrossRef

31.

Razavian M, Tavakoli S, Zhang J, Nie L, Dobrucki LW, Sinusas AJ, et al. Atherosclerosis plaque heterogeneity and response to therapy detected by in vivo molecular imaging of matrix metalloproteinase activation. J Nucl Med. 2011;52:1795–802. doi:10.2967/jnumed.111.092379.PubMedCentralPubMedCrossRef

Title: Targeting post-infarct inflammation by PET imaging: comparison of 68Ga-citrate and 68Ga-DOTATATE with 18F-FDG in a mouse model
Authors: James T. Thackeray
Jens P. Bankstahl
Yong Wang
Mortimer Korf-Klingebiel
Almut Walte
Alexander Wittneben
Kai C. Wollert
Frank M. Bengel
Publication date: 01-02-2015
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 2/2015
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-014-2884-6

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Targeting post-infarct inflammation by PET imaging: comparison of ⁶⁸Ga-citrate and ⁶⁸Ga-DOTATATE with ¹⁸F-FDG in a mouse model

Abstract

ᅟ

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

ᅟ

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2015

Prognostic value of volumetric parameters of 18F-FDG PET in non-small-cell lung cancer: a meta-analysis

The great mimicker: an extensive bone sarcoidosis

The value of 18F-fluoride PET/CT in the assessment of screw loosening in patients after intervertebral fusion stabilization

Prospective evaluation of a new protocol for the provisional use of perfusion imaging with exercise stress testing

The impact of nodal tumour burden on lymphoscintigraphic imaging in patients with melanomas

[68Ga]PSMA-HBED uptake mimicking lymph node metastasis in coeliac ganglia: an important pitfall in clinical practice