Original article
Quantitative analysis of [carbonyl-11C]WAY-100635 PET studies

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Abstract

ABSTRACT. [carbonyl-11C]WAY-100635 {[11C]N-(2-(4-(2-methoxyphenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl)cyclohexanecarboxamide} is a positron-emission tomography (PET) radioligand for in vivo imaging of the 5-hydroxytryptamine1A (5-HT1A) receptor. This paper assesses and summarises various different modeling strategies for the quantitative analysis of the radioligand. The models considered are based on a compartmental description of the ligands behaviour and include both plasma input analyses, requiring the additional monitoring of blood activity, and a reference tissue approach, which relies solely on the tomographic tissue data. Parameter estimates of specific binding are presented for a set of test-retest data, obtained from six normal volunteers who were scanned on two separate occasions, allowing for an assessment of normal binding values and their reproducibility.

Introduction

A positron-emission tomography (PET) radioligand for the 5-hydroxytryptamine1A (5-HT1A) receptor is of great interest to psychiatry because it is thought that 5-HT1A receptors play a major role in psychiatric disorders, such as anxiety, depression, dementia, and schizophrenia. WAY-100635 [N-(2-(4-methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl)cyclohexanecarboxamide] was developed as the first potent silent 5-HT1A receptor antagonist 7, 17 with excellent selectivity in vitro and in rodents ex vivo 14, 20, 27.

The PET radioligand [carbonyl-11C]WAY-100635 has demonstrated more favourable characteristics (28) for quantification than the previously available [O-methyl-11C]WAY-100635 (29). These benefits stem from the increased specific to nonspecific signal, which is consistent with a reduction in the blood-brain barrier penetration of labeled metabolites (26). These advantageous properties of [carbonyl-11C]WAY-100635 have facilitated quantification of 5-HT1A receptor binding 6, 10, 32, which is achieved via the application of biomathematical modeling techniques to the dynamic PET data.

This paper summarises the assessment of various modeling approaches and plasma and reference tissue methods, using a set of test-retest data that was acquired from six normal volunteers. This allows for an investigation of quantification methods in terms of inter- and intrasubject reproducibility (21). Also addressed here are comments about the sensitivity of the simplified reference tissue method to changes in flow when the compartmental description for the radioligand requires more than a single-tissue compartment (32) through additional simulation studies.

Ultimately, the complications of accurately estimating the plasma input function in conjunction with results yielded from the test-retest data set led to the conclusion that a simplified reference tissue approach was a suitable method for the quantification of [carbonyl-11C]WAY-100635. The reference tissue approach has been implemented at the voxel level and parametric images of binding obtained for both rat 11, 13 and human studies (10). A human [carbonyl-11C]WAY-100635 template (24) has been developed that allows for spatial normalisation of individual [carbonyl-11C]WAY-100635 binding maps into a stereotaxic space, facilitating subsequent statistical analyses on a voxel basis.

To date quantitative analyses of [carbonyl-11C]WAY-100635 have been used in human studies to demonstrate occupancy of 5-HT1A receptors by various drugs (30) and also to indicate reduced binding in studies of depression 4, 31. A study in rats has demonstrated occupancy of 5-HT1A receptors by pindolol and has enabled the production of parametric images of saturation kinetics 11, 13. Furthermore, this study, along with two similar studies in humans 23, 30, indicates a differential behavior of pindolol at the presynaptic (raphe nucleus) as compared to postsynaptic binding sites.

Section snippets

Human studies

Six normal male volunteers were scanned twice within an interval of 2 to 14 weeks (age: 22–47 years, weight: 65–80 kg). These volunteers were not on any medication and had no previous history of psychiatric disorder. All subjects gave informed consent. Dynamic scans were acquired in 3-D mode on an ECAT 953B PET scanner (Siemens/CTI, Knoxville, TN, USA) following an intravenous bolus administration of [carbonyl-11C]WAY-100635. Blood was sampled continuously via the radial artery and metabolite

Results

The radioligand is delivered effectively to the brain with an extraction of approximately 25%. Direct estimates of the individual rate constants or BP proved difficult with plasma data (10).

All other specific binding parameters derived from the one- and two-tissue compartmental models and the reference tissue model produced values in reasonable agreement with each other (see Table 1) and the known rank order of 5-HT1A receptor concentration (12). Of the plasma input analyses the two-tissue

Discussion

This paper describes some of the stages in the analysis of a new radioligand for PET with specific application to [carbonyl-11C]WAY-100635. The goal is ultimately to define a parsimonious model for the kinetic analysis of the radioligand and to present this data in an effective way (e.g., parametric images). In assessing a novel radioligand it is necessary to consider many factors, including:

  • Is the radioligand selective for the receptor type of interest? This might be answered by in vitro and

Acknowledgements

The authors are grateful to the Human Frontier Science Programme Organisation for support to the MRC Cyclotron Unit (grant no. RG0235/1998-B).

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