Comparison of [18F]altanserin and [18F]deuteroaltanserin for PET imaging of serotonin2A receptors in baboon brain: pharmacological studies
Introduction
From the time of the first in vivo human planar image of a radiolabeled hallucinogen which primarily displayed the whole body distribution of the serotonin 5-HT2A receptor, [35] considerable efforts have been applied towards the development of a selective radiotracer for PET and/or SPECT imaging of the brain 5-HT2A receptor. While several radiotracers have been developed to date, their utility for in vivo imaging has been limited due to high nonspecific binding or inadequate pharmacological selectivity over the dopamine D2 and/or 5-HT2c receptor [4], [7], [38]. Recently, major advances towards selective imaging of brain 5-HT2A receptors occurred with the development of [18F]altanserin, which demonstrated improved pharmacological specificity for binding to 5-HT2A receptors, with greater than 100- and 45-fold selectivity over D2 and 5-HT2C receptors, respectively [1], [2], [13], [16], [41]. The value of [18F]altanserin as a PET 5-HT2A radiotracer has been supported by its high specific brain uptake [3], [15], [34], relatively long half-life that permits equilibrium imaging using a bolus-plus-constant infusion paradigm [43], reasonable target to background ratios [3], [15], [34], [43], and reliable test-retest measures [37]. Despite these attributes, quantitative in vivo imaging of 5-HT2A receptors with [18F]altanserin has been hindered by the generation of lipophilic radiometabolites which cross the blood-brain barrier. While not pharmacologically active, these metabolites increase nondisplaceable uptake and may hinder reliable quantitation [1], [20], [27], [40].
Recently, a deuterated analog of [18F]altanserin was synthesized in effort to decrease the rate of metabolism and production of radioactive metabolites (Fig. 1). Deuteration does not alter the pharmacological specificity or the neuroanatomical distribution of the radiotracer, however it may decrease the rate of metabolism if transient cleavage of the carbon-hydrogen bond is involved in the rate limiting or rate-contributing step in the metabolism of the parent radiotracer because the carbon-deuterium bond is more difficult to break than the carbon-hydrogen bond. In keeping, a preliminary study in humans demonstrated a 29% higher ratio of parent to labeled metabolites in plasma for [18F]deuteroaltanserin compared to [18F]altanserin suggesting that deuteration induced a modest but distinct reduction in the rate of metabolism of altanserin [42]. Despite a slower rate of metabolism in humans, administration of [18F]deuteroaltanserin by the bolus plus constant infusion paradigm permits equilibrium imaging of 5-HT2A receptors [44] similar to [18F]altanserin [43]. In the present study, the regional distribution, metabolic stability, and pharmacological specificity of [18F]deuteroaltanserin brain uptake was examined and compared to [18F]altanserin in baboons using a constant infusion paradigm to achieve equilibrium receptor binding conditions.
Section snippets
Radiochemistry
[18F]Altanserin and [18F]deuteroaltanserin were prepared in a remote-control system as previously described [39], [41]. For the studies herein, the overall radiochemical yields determined at the end of bombardment were 19.0 ± 5.2% and 20.8 ± 8.9%, with radiochemical purity of 95.7 ± 3.3% and 95.9 ± 2.5% for [18F]altanserin (n = 8; mean ± SD) and [18F]deuteroaltanserin (n = 14; mean ± SD), respectively. At the end of the synthesis, the specific activities were 233 ± 149 and 291 ± 177 GBq/μmol
Neuroanatomical distribution
Visualization of the regional distributions of both radiotracers indicated that the neuroanatomical distribution of [18F]deuteroaltanserin activity was identical to that of [18F]altanserin. High uptake was found in cortical regions, including cingulate, frontal, parietal, insular, occipital, and temporal cortices. Both [18F]altanserin and [18F]deuteroaltanserin activity levels were virtually nondetectable in the striatum and cerebellum (data not shown).
Equilibrium imaging
The ability of [18F]altanserin and [18
Discussion
In the present study, the PET 5-HT2A receptor radiotracer [18F]deuteroaltanserin was evaluated and compared to its non-deuterated derivative [18F]altanserin in nonhuman primates. Equilibrium imaging by administration of the radiotracer using the bolus plus constant infusion paradigm indicated that both radiotracers achieved steady-state between 4 and 6 h. Assessment of the metabolism of both radiotracers by comparison of the total parent and free parent to total metabolite ratios demonstrated
Summary
The present study demonstrates that the deuterated derivative of the 5-HT2A PET radiotracer [18F]altanserin, ([18F]deuteroaltanserin) exhibits high brain uptake with a neuroanatomical signature characteristic of 5-HT2A receptor distribution and exhibits reasonable pharmacological specificity in vivo. Elevations in extrasynaptic 5-HT induced by S (+)-fenfluramine failed to alter cortical uptake indicating that [18F]deuteroaltanserin binding is insensitive to endogenous 5-HT levels. Overall, the
Acknowledgements
The authors would like to express sincere gratitude to Louis Amici and Nina Sheung for metabolite analysis, and Christine Cooper and Lisa Mauzy for their expertise in nuclear technology of PET imaging, and to Richard Feinn for assistance in image analysis. This grant was supported in part by funds from the NIH (MH58620 and MH30929), the Department of Veterans Affairs (Depression Research Enhancement Award Program, and the Japan Foundation for Aging and Health (Professor S. Yamawaki, Hiroshima
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