Synthesis and biological evaluation of 68Ga-bis-DOTA-PA as a potential agent for positron emission tomography imaging of necrosis.

Abstract

INTRODUCTION:

Necrosis is a form of cell death that occurs in a variety of pathological conditions but can also be the result of therapy in cancer treatment. A radiotracer that could image necrotic cell death using PET could therefore be a useful tool to provide relevant information on the disease activity or therapeutic efficacy and assist in diagnosis and therapy management of several disorders. Pamoic acid derivatives have previously been reported to show a selective uptake in tissue undergoing cellular death via necrosis. In this study 4,4'-methylene-bis(2-hydroxy-3-naphthoic hydrazide) (pamoic acid bis-hydrazide) was conjugated to the macrocyclic ligand DOTA and labeled with the generator produced positron emitter (68)Ga. The resulting complex ((68)Ga-bis-DOTA-PA; (68)Ga-3) was evaluated as a potential radiotracer for imaging tissues undergoing cellular death via necrosis.

METHODS:

Bis-DOTA-PA was synthesized and labeled with (68)Ga. Biodistribution of (68)Ga-3 and analysis of plasma were studied in normal NMRI mice. Binding of the complex to necrotic tissue was first evaluated by in vitro autoradiography. Further evaluation of the uptake in necrotic tissue was performed in two different models of necrosis using microPET imaging in correlation with ex vivo autoradiography, biodistribution studies and histochemical staining. A biodistribution study in a mouse model of hepatic apoptosis was performed to study the selectivity of the uptake of (68)Ga-bis-DOTA-PA in necrotic tissue.

RESULTS:

(68)Ga-3 was obtained with a decay-corrected radiochemical yield of 51.8% ± 5.4% and a specific activity of about 12 GBq/μmol. In normal mice, the complex was slowly cleared from blood, mainly through the renal pathway, and showed high in vivo stability. (68)Ga-bis-DOTA-PA displayed high and selective uptake in necrotic tissue and allowed imaging of necrotic tissue using microPET.

CONCLUSION:

(68)Ga-3 was synthesized and characterized. In vitro, in vivo and ex vivo studies showed that the complex displays high and selective uptake in tissue undergoing cellular death via necrosis.

• Authors: Kristof Prinsen, Marlein M Cona, Bernard J Cleynhens, Junjie Li, Hubert Vanbilloen, Natalia Dyubankova, Eveline Lescrinier, Yicheng Ni, Guy M Bormans, Alfons M Verbruggen
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 40 Issue 6 Pg. 816-22 (Aug 2013) ISSN: 1872-9614 [Electronic] United States
• PMID: 23915800 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Gallium Radioisotopes
• Heterocyclic Compounds, 1-Ring
• Naphthols
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• pamoic acid

Topics

• Animals
• Chemistry Techniques, Synthetic
• Gallium Radioisotopes
• Heterocyclic Compounds, 1-Ring (chemistry, pharmacokinetics)
• Liver (diagnostic imaging, pathology)
• Male
• Mice
• Naphthols (chemistry)
• Necrosis (diagnostic imaging)
• Positron-Emission Tomography (methods)
• Radiochemistry
• Rats