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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.

journal_name

Nucl Med Biol

journal_title

Nuclear medicine and biology

authors

Prinsen K,Cona MM,Cleynhens BJ,Li J,Vanbilloen H,Dyubankova N,Lescrinier E,Ni Y,Bormans GM,Verbruggen AM

doi

10.1016/j.nucmedbio.2013.04.011

subject

Has Abstract

pub_date

2013-08-01 00:00:00

pages

816-22

issue

eissn

0969-8051

issn

1872-9614

pii

S0969-8051(13)00104-2

journal_volume

pub_type

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