Comparison of [18F]altanserin and [18F]deuteroaltanserin for PET imaging of serotonin2A receptors in baboon brain: pharmacological studies

https://doi.org/10.1016/S0969-8051(00)00212-2Get rights and content

Abstract

The regional distribution in brain, distribution volumes, and pharmacological specificity of the PET 5-HT2A receptor radiotracer [18F]deuteroaltanserin were evaluated and compared to those of its non-deuterated derivative [18F]altanserin. Both radiotracers were administered to baboons by bolus plus constant infusion and PET images were acquired up to 8 h. The time-activity curves for both tracers stabilized between 4 and 6 h. The ratio of total and free parent to metabolites was not significantly different between radiotracers; nevertheless, total cortical RT (equilibrium ratio of specific to nondisplaceable brain uptake) was significantly higher (34–78%) for [18F]deuteroaltanserin than for [18F]altanserin. In contrast, the binding potential (Bmax/KD) was similar between radiotracers. [18F]Deuteroaltanserin cortical activity was displaced by the 5-HT2A receptor antagonist SR 46349B but was not altered by changes in endogenous 5-HT induced by fenfluramine. These findings suggest that [18F]deuteroaltanserin is essentially equivalent to [18F]altanserin for 5-HT2A receptor imaging in the baboon.

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

References (44)

  • Baldwin, R., Tan, P. and CH van Dyck et al., (1998) Radiometabolites of [18F]altanserin in rats and humans:...
  • Barnes, N. and Sharp, T. (1999) A review of central 5-HT receptors and their function, Neuropharmacology, 38,...
  • Biver, F., Goldman, S., Luxen, A., Monclus, M., Forestini, M., Mendlewics, J. and Lotstra, F. (1994) Multicompartmental...
  • Blin, J., Pappata, S., Kiyosawa, M., Crouzel, C. and Baron, J. (1988) [18F]Setoperone: a new high-affinity ligand for...
  • Bonhaus, D., Bach, C., DeSouza, A., Salazar, F., Matsuoka, B., Zuppan, P., Chan, H. and Eglen, R. (1995) The...
  • Burnet, P., Eastwood, S., Lacey, K. and Harrison, P. (1995) The distribution of 5-HT1A and 5-HT2A receptor mRNA in...
  • Coenen, H., Wienhard, K., Stocklin, G., Laufer, P., Hebold, I., Pawlik, G. and Heiss, W. (1988) PET measurement of D2...
  • Darchen, F., Scherman, D., Laduron, P. and Henry, J. (1988) Ketanserin binds to the monoamine transporter of chromaffin...
  • Dwivedi, Y. and Pandey, G. (1998) Quantitation of 5HT2A receptor mRNA in human postmortem brain using competitive...
  • Friston, K., Ashburner, J., Poine, J., Frith, C., Heather, J. and Frackowiak, R., Spatial registration and...
  • Fuller, R., Snoody, H. and Robertson, D., Mechanisms of effects of d-fenfluramine on brain serotonin in rats: uptake...
  • Garattini, S., Caccia, S., Mennini, T., Samanin, R., Consolo, S. and Ladinsky, H. (1979) Biochemical pharmacology of...
  • Hoyer, D. (1988) Functional correlates of serotonin 5-HT1 recognition sites. J Receptor Res, 8,...
  • Laruelle, M., Abi-Dargham,A. and Innis, R. (1998) Imaging receptor occupancy by endogenous transmitters in humans. In...
  • Lemaire, C., Cantineau, R., Guillaume, M., Plenevaux, A. and Christiaens, L. (1991) Fluorine-18-Altanserin: a...
  • Leysen, J. (1989) Use of 5-HT receptor agonists and antagonists for the characterization of their respective receptor...
  • Leysen, J., Awouters, F., Kennis, L., Laduron, P., Vanderberk, J. and Janssen, P.(1981) Receptor binding profile of R...
  • Leysen, J., Eens, A., Gommeren, W., Gompel, P.V., Wynants, J. and Janssen, P. (1988) Identification of nonserotonergic...
  • Leysen, J., Niemegeers, C., Nueten, J.V. and Laduron, P. (1982) [3H]Ketanserin (R 41 468), a selective 3H-ligand for...
  • LoPresti, B., Holt, D., Mason, N., Huang, Y., Ruszkiewicz, J., Perevuznik, J., Price, J., Smith, G., Davis, J. and...
  • Luabeya, M., Maloteauz, J. and Laduron, P. (1984) Regional and cortical laminar distribution of serotonin S2,...
  • Mennini, T., Garattini, S. and Caccia, S. (1985) Anorectic effect of fenfluramine isomers and metabolites: Relationship...
  • Cited by (42)

    • Preclinical evaluation of [<sup>18</sup>F]D3FSP, deuterated AV-45, for imaging of β-amyloid in the brain

      2021, Nuclear Medicine and Biology
      Citation Excerpt :

      To observe high KIE by deuterium substitution, it is necessary that the C–H cleavage step is at least partially rate-limiting among the multistep enzyme-catalyzed metabolism. The efforts to exploit isotope effects in the design of radiotracers resulted in a mixed outcome [30–33]. Deuterium substitution in small molecules often does not result in a change of the shape, size, charge or target pharmacology.

    • Serotonin receptor imaging by <sup>18</sup>F-PET

      2018, Fluorine in Life Sciences: Pharmaceuticals, Medicinal Diagnostics, and Agrochemicals Progress in Fluorine Science Series
    • Imaging of Neurochemical Transmission in the Central Nervous System

      2014, Imaging of the Human Brain in Health and Disease
    • Characterization of [<sup>11</sup>C]Cimbi-36 as an agonist PET radioligand for the 5-HT<inf>2A</inf> and 5-HT<inf>2C</inf> receptors in the nonhuman primate brain

      2014, NeuroImage
      Citation Excerpt :

      Indeed, dopamine D2 and D3 receptor agonist radioligands have been found to have an enhanced sensitivity to endogenous dopamine concentrations than antagonist radioligands (Ginovart et al., 2006; Narendran et al., 2004, 2010; Seneca et al., 2006; Shotbolt et al., 2012). Since 5-HT2A receptor antagonist PET radioligands have no or very limited sensitivity to changes in endogenous serotonin concentrations (Hirani et al., 2003; Pinborg et al., 2004; Quednow et al., 2012; Staley et al., 2001), an agonist radioligand may provide additional value to the available 5-HT2A receptor antagonist radioligands. Only recently, the first agonist radioligands for the 5-HT2A receptor were described, with [11C]Cimbi-36 reported as the most promising so far (Ettrup et al., 2010, 2011).

    View all citing articles on Scopus
    View full text