title: Synthesis and biological evaluation of 68Ga-bis-DOTA-PA as a potential agent for positron emission tomography imaging of necrosis.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  (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.affiliation: KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Radiopharmacy, Herestraat 49, Box 821, BE-3000, Leuven, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Prinsen
authors.forename: Marlein M
authors.initials: MM
authors.lastname: Cona
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Cleynhens
authors.forename: Junjie
authors.initials: J
authors.lastname: Li
authors.forename: Hubert
authors.initials: H
authors.lastname: Vanbilloen
authors.forename: Natalia
authors.initials: N
authors.lastname: Dyubankova
authors.forename: Eveline
authors.initials: E
authors.lastname: Lescrinier
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Ni
authors.forename: Guy M
authors.initials: GM
authors.lastname: Bormans
authors.forename: Alfons M
authors.initials: AM
authors.lastname: Verbruggen
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000493:pharmacokinetics; D008099:Liver / Q000000981:diagnostic imaging / Q000473:pathology*; D008297:Male; D051379:Mice; D009284:Naphthols / Q000737:chemistry*; D009336:Necrosis / Q000000981:diagnostic imaging; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D051381:Rats
chemical_list: D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D009284:Naphthols; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C004368:pamoic acid
keywords: Cell death; Gallium-68; Necrosis; PET; Pamoic acid