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. 2014 Jul 16;5(7):519-24.
doi: 10.1021/cn500024c. Epub 2014 Apr 23.

A novel fluorine-18 β-fluoroethoxy organophosphate positron emission tomography imaging tracer targeted to central nervous system acetylcholinesterase

Shelly L James  1 , S Kaleem Ahmed, Stephanie Murphy, Michael R Braden, Yamina Belabassi, Henry F VanBrocklin, Charles M Thompson, John M Gerdes
Affiliations

A novel fluorine-18 β-fluoroethoxy organophosphate positron emission tomography imaging tracer targeted to central nervous system acetylcholinesterase

Shelly L James et al. ACS Chem Neurosci. .

Abstract

Radiosynthesis of a fluorine-18 labeled organophosphate (OP) inhibitor of acetylcholinesterase (AChE) and subsequent positron emission tomography (PET) imaging using the tracer in the rat central nervous system are reported. The tracer structure, which contains a novel β-fluoroethoxy phosphoester moiety, was designed as an insecticide-chemical nerve agent hybrid to optimize handling and the desired target reactivity. Radiosynthesis of the β-fluoroethoxy tracer is described that utilizes a [(18)F]prosthetic group coupling approach. The imaging utility of the [(18)F]tracer is demonstrated in vivo within rats by the evaluation of its brain penetration and cerebral distribution qualities in the absence and presence of a challenge agent. The tracer effectively penetrates brain and localizes to cerebral regions known to correlate with the expression of the AChE target. Brain pharmacokinetic properties of the tracer are consistent with the formation of an OP-adducted acetylcholinesterase containing the fluoroethoxy tracer group. Based on the initial favorable in vivo qualities found in rat, additional [(18)F]tracer studies are ongoing to exploit the technology to dynamically probe organophosphate mechanisms of action in mammalian live tissues.

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Figures

Figure 1
Figure 1
Select organophosphate (OP) agents.
Scheme 1
Scheme 1. OP-Inhibition of AChE by Serine (ser) Phosphorylation and Subsequent Reactivation or Aging Processes, Where X Is a Leaving Group and Y Is Either an Alkyl or Alkoxy Moiety
Scheme 2
Scheme 2. Radiosynthesis of PET Imaging Tracer [18F]4
Figure 2
Figure 2
Averaged (n = 3) decay-corrected, subject normalized (SUV), radioactivity versus time curves in rat brain with standard error measure bars determined after i.v. injection of tracer [18F]4: solid lines from baseline (tracer alone) scans; broken lines from challenged scans (nonradioactive 4, 2.0 mg/kg, 10 min prior to tracer; see the Supporting Information for an expanded Y-axis plot of these challenge curves); with select regions of interest defined per the legend as hind brain/brain stem (BS), caudate-putamen (CP), frontal cortex (FrCtx), midbrain (MB), TH thalamus (TH), and cerebellum (CE).
Figure 3
Figure 3
Rat sagittal brain and partial spine view (anterior left, posterior right; −0.57 mm from midline) of coregistered PET (colored) and CT (white, gray, black) data; with PET radioactivity averaged over all time frames (0–120 min) post [18F]4 i.v. injection (1.14 mCi), displayed using NIH color table (0.0–4.0 SUV global thresholds); cerebral regions shown as ellipses and labeled per Figure 2 definitions.
Figure 4
Figure 4
Typical radioactivity (decay corrected and subject normalized as SUV) versus time curves for select peripheral rat tissues (heart, lung and liver; per legend) after administration of 1.8 mCi of [18F]4.
See this image and copyright information in PMC

References

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