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

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

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.

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Acknowledgments

The authors thank the preclinical molecular imaging and radiochemistry staff of the Department of Nuclear Medicine for their technical assistance. J.T.T. is supported by fellowships from the German Academic Exchange Service (DAAD) and the Canadian Institutes of Health Research. This project was partially funded by the REBIRTH-2 Cluster of Excellence and by EU FP7 grant PIRG08-GA-2010-276889 (F.M.B.).

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Authors and Affiliations

  1. Department of Nuclear Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    James T. Thackeray, Jens P. Bankstahl, Almut Walte, Alexander Wittneben & Frank M. Bengel

  2. Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

    James T. Thackeray, Yong Wang, Mortimer Korf-Klingebiel & Kai C. Wollert

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  1. James T. Thackeray
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Correspondence to Frank M. Bengel.

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Suppl Fig 1

Experimental design and imaging protocols. (a) Experimental timeline with MI at day 0 followed by PET imaging at 3, 5 and 7 days post-MI. Mice were randomized and serially imaged with different sequential tracers as indicated horizontally (i.e. a different tracer used in each individual subject for each time point). (b) Imaging protocols for 68Ga-citrate and 68Ga-DOTATATE and (c) 18F-FDG acquisitions (acq) and 57Co transmission scans (Tx) under isoflurane (isofl) or ketamine/xylazine (KX) anaesthesia. 13N-Ammonia (NH3) PET scans and contrast CT imaging was performed only on day 7 post-MI. (PPTX 69 kb).

Suppl Fig 2

Late frame myocardial 68Ga-citrate distribution. (a) Representative parametric SUV-scaled 68Ga-citrate transaxial, coronal, and sagittal myocardial images obtained at 60-90 min, 120-150 min, and 180-210 min after injection in healthy control mice. (b) Semi-quantitative analysis of whole left ventricle myocardium and left atrial cavity (blood pool) SUV in late frames demonstrates persistence in blood pool over 3h after injection. (PPTX 1386 kb)

Suppl Fig 3

Early frame myocardial 68Ga-DOTATATE distribution. (a) Representative transaxial, coronal, and sagittal myocardial image at 7-10 min after injection demonstrates low myocardial activity early after tracer injection in a mouse 3 days post-MI. (b) Semi-quantitative analysis of whole myocardium and blood pool activity at 7-10 min after injection. (c) Early frame time-activity curves of kidney and urinary bladder demonstrate rapid renal clearance of 68Ga-DOTATATE in post-MI mice. (PPTX 478 kb)

Suppl Fig 4

Whole body distribution of 18F-FDG in healthy and post-infarct mice under ketamine/xylazine anaesthesia. Representative 18F-FDG images; left, anterior 3D PET/CT maximum intensity projection in healthy control mice under isoflurane or ketamine-xylazine (KX) anaesthesia; right, parametric myocardial images in healthy mice under isoflurane or with suppression of cardiomyocyte uptake by KX. (PPTX 1380 kb)

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Thackeray, J.T., Bankstahl, J.P., Wang, Y. et al. Targeting post-infarct inflammation by PET imaging: comparison of 68Ga-citrate and 68Ga-DOTATATE with 18F-FDG in a mouse model. Eur J Nucl Med Mol Imaging 42, 317–327 (2015). https://doi.org/10.1007/s00259-014-2884-6

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