title: Preclinical characterization of 5-amino-4-oxo-[6-11C]hexanoic acid as an imaging probe to estimate protoporphyrin IX accumulation induced by exogenous aminolevulinic acid.
abstract: Preoperative noninvasive imaging to estimate the quantity and spatial distribution of protoporphyrin IX (PpIX) accumulation in tumors induced by 5-aminolevulinic acid (ALA) administration is expected to improve the efficacy of ALA-based fluorescence-guided resection and photo- and sonodynamic therapies. PpIX synthesis from exogenous ALA has been reported to be regulated by ALA influx or ALA dehydratase (ALAD) activity, which catalyzes the first step of the synthesis. In this study, we characterized the properties of a (11)C-labeled ALA analog, 5-amino-4-oxo-[6-(11)C]hexanoic acid ((11)C-MALA), as a PET tracer to estimate PpIX accumulation.
  
  
  METHODS
  In vitro uptake of (11)C-MALA and (3)H-ALA was determined in 5 tumor cell lines after 10-min incubation with each tracer at 37°C. The expression levels of ALAD were determined by Western blot analysis. In vivo distribution and dynamic PET studies were conducted in tumor-bearing mice. In vitro and in vivo accumulation of ALA-induced PpIX was determined by measuring fluorescence in extracts of cells or tumors.
  
  
  RESULTS
  In vitro uptake of (11)C-MALA in 5 tumor cell lines was correlated with ALAD expression levels and PpIX accumulation. In vivo biodistribution and dynamic PET studies showed that (11)C-MALA was rapidly incorporated into tumors, and the tumor-to-muscle ratio of (11)C-MALA at 1 min after injection was significantly correlated with that of (3)H-ALA. (11)C-MALA in tumors was continuously decreased thereafter, and the elimination rate of (11)C-MALA from AsPC-1 tumors with the highest ALAD expression level was slower than from other tumors with lower expression levels. These results suggest that the influx and intracellular retention of (11)C-MALA reflect ALA influx and ALAD expression levels, respectively. Tumor accumulation of (11)C-MALA at 60 min after injection was strongly correlated with PpIX accumulation in tumor tissues.
  
  
  CONCLUSIONS
  (11)C-MALA PET has the potential to noninvasively estimate the quantitative and spatial accumulation of exogenous ALA-induced PpIX.
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Suzuki
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan a_tsuji@nirs.go.jp.
authors.forename: Atsushi B
authors.initials: AB
authors.lastname: Tsuji
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; and Department of Integrative Brain Imaging, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; and.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Sudo
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; and.
authors.forename: Maki
authors.initials: M
authors.lastname: Okada
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Sugyo
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; and.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Arano
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D000614:Aminocaproates / Q000737:chemistry* / Q000493:pharmacokinetics; D000622:Aminolevulinic Acid / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy; D049268:Positron-Emission Tomography / Q000379:methods; D011524:Protoporphyrins / Q000737:chemistry*
chemical_list: D000614:Aminocaproates; D011524:Protoporphyrins; C031350:4-keto-5-amino-6-hydroxyhexanoic acid; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX
keywords: 11C-MALA; 5-aminolevulinic acid; aminolevulinic acid dehydratase; photodynamic therapy; sonodynamic therapy