A promising carbon-11-labeled sphingosine-1-phosphate receptor 1-specific PET tracer for imaging vascular injury.

Abstract

BACKGROUND:

Sphingosine-1-phosphate receptor 1 (S1PR1) is highly expressed in vascular smooth muscle cells from intimal lesions. PET imaging using S1PR1 as a biomarker would increase our understanding of its role in vascular pathologies including in-stent restenosis.

METHODS:

The S1PR1 compound TZ3321 was synthesized for in vitro characterization and labeled with Carbon-11 for in vivo studies. The biodistribution of [11C]TZ3321 was evaluated in normal mice; microPET and immunohistochemistry (IHC) studies were performed using a murine femoral artery wire-injury model of restenosis.

RESULTS:

The high potency of TZ3321 for S1PR1 (IC 50 = 2.13 ± 1.63 nM), and high selectivity (>1000 nM) for S1PR1 over S1PR2 and S1PR3 were confirmed. Biodistribution data revealed prolonged retention of [11C]TZ3321 in S1PR1-enriched tissues. MicroPET imaging of [11C]TZ3321 showed higher uptake in the wire-injured arteries of ApoE-/- mice than in injured arteries of wild-type mice (SUV 0.40 ± 0.06 vs 0.28 ± 0.04, n = 6, P < .001); FDG-PET showed no difference (SUV 0.98 ± 0.04 vs 0.94 ± 0.01, n = 6, P > .05). Post-PET autoradiography showed >4-fold higher [11C]TZ3321 retention in the injured artery of ApoE-/- mice than in wild-type mice. Subsequent IHC staining confirmed higher expression of S1PR1 in the neointima of the injured artery of ApoE-/- mice than in wild-type mice.

CONCLUSIONS:

This preliminary study supports the potential use of PET for quantification of the S1PR1 expression as a biomarker of neointimal hyperplasia.

• Authors: Hongjun Jin, Hao Yang, Hui Liu, Yunxiao Zhang, Xiang Zhang, Adam J Rosenberg, Yongjian Liu, Suzanne E Lapi, Zhude Tu
• Journal: Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology (J Nucl Cardiol) Vol. 24 Issue 2 Pg. 558-570 (04 2017) ISSN: 1532-6551 [Electronic] United States
• PMID: 26843200 (Publication Type: Journal Article)

Chemical References

• Carbon Radioisotopes
• Carbon-11
• Radiopharmaceuticals
• Receptors, Lysosphingolipid
• S1pr1 protein, mouse
• Sphingosine-1-Phosphate Receptors

Topics

• Animals
• Carbon Radioisotopes (pharmacokinetics)
• Feasibility Studies
• Female
• Graft Occlusion, Vascular (diagnostic imaging, metabolism)
• Humans
• Image Enhancement (methods)
• Male
• Metabolic Clearance Rate
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Diagnostic Techniques (methods)
• Organ Specificity
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (pharmacokinetics)
• Receptors, Lysosphingolipid (metabolism)
• Reproducibility of Results
• Sensitivity and Specificity
• Sphingosine-1-Phosphate Receptors
• Tissue Distribution