Radioiodinated PARP1 tracers for glioblastoma imaging Journal Article


Authors: Salinas, B.; Irwin, C. P.; Kossatz, S.; Bolaender, A.; Chiosis, G.; Pillarsetty, N.; Weber, W. A.; Reiner, T.
Article Title: Radioiodinated PARP1 tracers for glioblastoma imaging
Abstract: Background: Although the understanding of the genetic and molecular basis of cancer has advanced significantly over the past several decades, imaging and treatment options for glioblastoma patients have been more limited (N Engl J Med 359:492-507, 2008). This is in part due to difficulties in diagnosing this disease early, combined with its diffuse, infiltrative growth. This study was aimed at the development of a novel diagnostic tool for glioblastoma through the synthesis of a small molecule based on radioiodinated poly(ADP-ribose)polymerase 1 (PARP1) targeted tracers. This PARP1 is a biomarker that is overexpressed in glioblastoma tissue, but has only low expression levels in the healthy brain (Neoplasia 16:432-40, 2014). Methods: A library of PARP1 inhibitors (iodo-PARPis) was synthesized. Based on their pharmacokinetic properties and nuclear PARP1 binding, the most successful inhibitor was radiolabeled with 131I and 124I. Biodistribution as well as imaging experiments were performed in orthotopic and subcutaneous mouse models of glioblastoma. Results: One member of our iodo-poly(ADP-ribose)polymerase 1 (PARP1) inhibitor library, I2-PARPi, shows promising biophysical properties for in vivo application. All synthesized tracers have IC<inf>50</inf> values in the nanomolar range (9 ± 2–107 ± 4 nM) and were able to inhibit the uptake of a fluorescent PARP1 inhibitor analog (PARPi-FL). I2-PARPi was able to reduce the uptake of PARPi-FL by 78 ± 4 % in vivo. In mouse models of glioblastoma, we show that the radioiodinated inhibitor analog has high uptake in tumor tissue (U251 MG xenograft, tumor, 0.43 ± 0.06 %ID/g; brain, 0.01 ± 0.00 %ID/g; muscle, 0.03 ± 0.01 %ID/g; liver, 2.35 ± 0.57 %ID/g; thyroid, 0.24 ± 0.06 %ID/g). PET and SPECT imaging performed in orthotopic glioblastoma models with [124I]- and [131I]-I2-PARPi showed selective accumulation in the tumor tissue. These results were also verified using autoradiography of tumor sections, which displayed focal selective uptake of the tracer in the tumor regions as confirmed by histology. The uptake could be blocked through pre-injection of excess unlabeled PARP1 inhibitor (Olaparib). Conclusions: We have successfully synthesized and radioiodinated the PARP1 selective tracer I2-PARPi. The novel tracer shows selective binding to tumor tissue, both in vitro and in models of glioblastoma, and has the potential to serve as a selective PET imaging agent for brain tumors. © 2015, Salinas et al.
Keywords: immunohistochemistry; controlled study; protein expression; unclassified drug; human cell; nonhuman; mass spectrometry; mouse; animal tissue; histology; glioblastoma; high performance liquid chromatography; pet; autoradiography; olaparib; radiochemistry; spect; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; 131i; 124i; hydrophobicity; priority journal; article; ic50; parp1; u251 mg; u87 mg; 4 (4 fluoro 3 (4 (2 (3 iodophenyl)acetyl)piperazine 1carbonyl)benzyl)phthalazin- (2h) one; 4 (4 fluoro 3 (4 (2 (4 iodophenyl)acetyl)piperazine 1 carbonyl)benzyl)phthalazin 1(2h) one; 4 (4 fluoro 3 (4 (3 (3 iodophenyl)propanoyl)piperazine 1arbonyl)benzyl)phthalazin 1(2h) one; 4 (4 fluoro 3 (4 (3 (4 iodophenyl)propanoyl)piperazine 1 carbonyl)benzyl) phthalazin 1(2h) one; 4 (4 fluoro 3 (4 (3 iodobenzoyl)piperazine 1 carbonyl)benzyl) phthalazin 1(2h) one; 4 (4 fluoro 3 (4 (4 iodobenzoyl)piperazine 1 carbonyl)benzyl)phthalazin 1(2h) one; plasma protein fraction; ct-spect scanner
Journal Title: EJNMMI Research
Volume: 5
ISSN: 2191-219X
Publisher: Springer  
Date Published: 2015-09-04
Start Page: 46
Language: English
DOI: 10.1186/s13550-015-0123-1
PROVIDER: scopus
PMCID: PMC4559561
PUBMED: 26337803
DOI/URL:
Notes: Export Date: 2 October 2015 -- Source: Scopus
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MSK Authors
  1. Gabriela Chiosis
    218 Chiosis
  2. Thomas Reiner
    71 Reiner
  3. Christopher P. Irwin
    10 Irwin
  4. Wolfgang Andreas Weber
    149 Weber
  5. Susanne   Kossatz
    24 Kossatz