Elsevier

Bioorganic & Medicinal Chemistry

Volume 18, Issue 22, 15 November 2010, Pages 7739-7745
Bioorganic & Medicinal Chemistry

Evaluation of [11C]metergoline as a PET radiotracer for 5HTR in nonhuman primates

https://doi.org/10.1016/j.bmc.2010.04.039Get rights and content

Abstract

Metergoline, a serotonin receptor antagonist, was labeled with carbon-11 in order to evaluate its pharmacokinetics and distribution in non-human primates using positron emission tomography. [11C]Metergoline had moderate brain uptake and exhibited heterogeneous specific binding, which was blocked by pretreatment with metergoline and altanserin throughout the cortex. Non-specific binding and insensitivity to changes in synaptic serotonin limit its potential as a PET radiotracer. However, the characterization of [11C]metergoline pharmacokinetics and binding in the brain and peripheral organs using PET improves our understanding of metergoline drug pharmacology.

Introduction

Metergoline is a relatively old ergot-derived drug that has been explored in a variety of medical applications,1 including seasonal depression2 and prolactin hormone regulation.3 It has also been used in veterinary medicine as a pregnancy termination drug for dogs.4 The pharmacological effects of metergoline have been primarily attributed to its interactions with the serotonin (5-hydroxytryptamine, (5HT)) system. Metergoline acts as an antagonist at many of the 5HT receptor subtypes (with binding affinities reported as low as 120 pM) and has also been shown to interact with certain dopamine receptors albeit with lower potency.5 Since initially reported in 1965,6 metergoline has been used in hundreds of behavioral pharmacology experiments as a probe for 5HT receptor function.7

We were initially attracted to metergoline during the development of a new method to label compounds with carbon-11, a positron-emitting isotope with a 20.4 min half life.8 During the course of these studies, which were aimed at direct fixation of 11CO2 in carbamates, we were able to synthesize [11C]metergoline with high efficiency and relative ease. Because of the interesting pharmacology associated with the use of metergoline as a serotonergic drug, we decided to characterize [11C]metergoline binding in the non-human primate brain using positron emission tomography (PET). This was in part prompted by an earlier in vitro characterization of tritium labeled metergoline.9

Nearly three decades ago, [3H]metergoline was explored as a ligand for serotonin receptor autoradiography and showed specific binding for serotonin receptors 10–400 times more sensitive to serotonin- than dopamine-receptor antagonists, depending on the brain region and blocking drug used. Although [3H]metergoline displayed suitable characteristics as a radioligand for 5HT receptors, it was never subsequently used for this purpose (perhaps due to the development of more sub-type specific radioligands).

While several serotonin ligands have been developed as PET radiotracers for various receptor subtypes (see Fig. 1 for examples), there remain limitations in the ability to probe the serotonin system using PET, primary among them being radiotracer sensitivity to synaptic serotonin concentration.10 In order to determine the potential of [11C]metergoline as a serotonin radiotracer and to characterize its binding in vivo, we examined its baseline pharmacokinetics and distribution in both the brain and peripheral organs as well changes in binding after pretreatment with unlabeled metergoline, altanserin, and citalopram.

Section snippets

Chemistry

Synthesis of a labeling precursor was accomplished by hydrogenolysis of metergoline, Scheme 1. The resulting amine (2) was isolated in nearly quantitative yield without chromatographic separation. Less than 0.1% of the starting material remained, an important consideration for PET imaging given that contaminating starting material would have a direct impact on radiotracer specific activity. The facile ‘deprotection’ of metergoline highlights one key advantage of using a carbon-11 carbamate

Conclusions

Metergoline can be efficiently and reproducibly labeled with carbon-11 using a DBU-mediated direct fixation of high specific activity 11CO2. [11C]Metergoline has good brain penetration and uptake in non-human primates, with kinetics suitable for quantitative analysis; however blocking studies revealed that [11C]metergoline exhibits a mixture of specific and non-specific binding which limits its usefulness as a radiotracer. [11C]Metergoline binding was not sensitive to pre-synaptic SERT blockade

General

[11C]Carbon dioxide was generated from a nitrogen/oxygen (1000 ppm) target (14N(p,α)11C) using an EBCO TR 19 cyclotron (Advanced Cyclotron Systems INC. Richmond, Canada). High performance liquid chromatography (HPLC) purification was performed by a Knauer HPLC system (Sonntek Inc., Woodcliff Lake, NJ, USA) with a model K-5000 pump, a Rheodyne 7125 injector, a model 87 variable wavelength monitor, and a NaI radioactivity detector.

Specific activity was determined by measuring the radioactivity and

Acknowledgments

This work was carried out at Brookhaven National Laboratory under contract DE-AC02-98CH10886 with the U.S. Department of Energy, supported by its Office of Biological and Environmental Research. J.M.H. was supported by an NIH Postdoctoral Fellowship (1F32EB008320) and through the Goldhaber Distinguished Fellowship program at BNL. The authors are grateful to Dr. Michael Schueller for cyclotron operation and the PET imaging team at BNL (Pauline Carter, Payton King, and Don Warner) for carrying

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