title: Synthesis and in vitro evaluation of novel nortropane derivatives as potential radiotracers for muscarinic m(2) receptors.
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 M(2) 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 M(2) receptor. 6β-acetoxynortropane and the novel derivatives were tested in vitro for affinity to the muscarinic M(1-3) receptors. The original 6β-acetoxynortropane displayed high affinity (K(i) = 70-90 nM) to M(2) receptors and showed good selectivity ratios to the M(1) (65-fold ratio) and the M(3) (70-fold ratio) receptors. All new derivatives showed reduced affinity to the M(2) subtype and loss of subtype selectivity. It is therefore concluded that the newly synthesized derivatives are not suitable for human SPECT imaging of M(2) receptors.
authors.affiliation: Department of Nuclear Medicine, Medical Center Alkmaar, Wilhelminalaan 12, 1815 JD Alkmaar, The Netherlands.
authors.forename: Remco J J
authors.initials: RJ
authors.lastname: Knol
authors.forename: Jan C
authors.initials: JC
authors.lastname: van den Bos
authors.forename: Anton G M
authors.initials: AG
authors.lastname: Janssen
authors.forename: Kora
authors.initials: K
authors.lastname: de Bruin
authors.forename: Berthe L F
authors.initials: BL
authors.lastname: van Eck-Smit
authors.forename: Jan
authors.initials: J
authors.lastname: Booij