Synthesis and In Vitro Evaluation of Novel Nortropane Derivatives as Potential Radiotracers for Muscarinic M2 Receptors

Remco J J Knol,Berthe L F Van Eck-Smit,Jan C Van Den Bos,Kora De Bruin,Jan Booij,Anton G M Janssen

doi:10.1155/2011/709416

Abstract

Disturbances of the cerebral cholinergic neurotransmitter system are present in neurodegenerative disorders. SPECT or PET imaging, using radiotracers that selectively target muscarinic receptor subtypes, may be of value for in vivo evaluation of such conditions. 6β-acetoxynortropane, a potent muscarinic M2 receptor agonist, has previously demonstrated nanomolar affinity and high selectivity for this receptor. Based on this compound we synthesized four nortropane derivatives that are potentially suitable for SPECT imaging of the M2 receptor. 6β-acetoxynortropane and the novel derivatives were tested in vitro for affinity to the muscarinic M1−3 receptors. The original 6β-acetoxynortropane displayed high affinity (K i = 70–90 nM) to M2 receptors and showed good selectivity ratios to the M1 (65-fold ratio) and the M3 (70-fold ratio) receptors. All new derivatives showed reduced affinity to the M2 subtype and loss of subtype selectivity. It is therefore concluded that the newly synthesized derivatives are not suitable for human SPECT imaging of M2 receptors.

Highlights

Central cholinergic disturbances are present in many neuropsychiatric and neurodegenerative diseases
In various forms of dementia, such as Alzheimer’s dementia (AD) or Lewy body dementia, cholinergic deficits in the brain [1, 2] are associated with cognitive decline [3,4,5] and are thought to precede clinical symptoms
In vivo assessment of the central cholinergic system in patients suffering from dementia by means of positron emission tomography (PET) or single photon emission computed tomography (SPECT) may be of value for early diagnosis or monitoring of such diseases, to predict response to cholinergic therapies or to evaluate effects of experimental drugs

Summary

Introduction

Central cholinergic disturbances are present in many neuropsychiatric and neurodegenerative diseases. The majority of the cholinergic deficits in these diseases arise from degenerative events in basal forebrain regions such as the nucleus basalis of Meynert [6, 7], which provides the cholinergic input of the cerebral cortex. In degenerative diseases such as AD, disruption of basal cholinergic forebrain projections leads to a presynaptic cholinergic defect in cortical brain areas [1, 8]. Molecular imaging of the cholinergic system of the brain requires radiotracers that ideally selectively target specific neuroreceptors of this neurotransmitter system, such as the muscarinic M2 receptor

Methods

Results

Conclusion