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Evaluation of σ-1 receptor radioligand 18F-FTC-146 in rats and squirrel monkeys using PET

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Michelle L James
  • Bin Shen
  • Nielsen, Carsten Haagen
  • Deepak Behera
  • Christine L Buckmaster
  • Christophe Mesangeau
  • Cristina Zavaleta
  • Pradeep K Vuppala
  • Seshulatha Jamalapuram
  • Bonnie A Avery
  • David M Lyons
  • Christopher R McCurdy
  • Sandip Biswal
  • Sanjiv S Gambhir
  • Frederick T Chin

UNLABELLED: The noninvasive imaging of σ-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F-FTC-146 for eventual clinical translation.

METHODS: The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, γ counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum.

RESULTS: Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F-FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents.

CONCLUSION: Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain.

OriginalsprogEngelsk
TidsskriftJournal of Nuclear Medicine
Vol/bind55
Udgave nummer1
Sider (fra-til)147-53
Antal sider7
ISSN0161-5505
DOI
StatusUdgivet - jan. 2014

ID: 132098743