Synthesis and in vitro evaluation of novel nortropane derivatives as potential radiotracers for muscarinic m(2) receptors.

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. 6ß-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. 6ß-acetoxynortropane and the novel derivatives were tested in vitro for affinity to the muscarinic M(1-3) receptors. The original 6ß-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.

Synthesis and evaluation of iodinated TZTP-derivatives as potential radioligands for imaging of muscarinic M2 receptors with SPET.

A series of iodinated thiadiazolyltetrahydro-1-methyl-pyridine (TZTP) compounds was synthesized and evaluated in vitro and in vivo as potential radioligands for imaging of the muscarinic M2 receptor subtype with SPET. One of these compounds, 5-(E)-iodopentenylthio-TZTP, has high in vitro affinity (Ki = 4.9 nM) and moderate selectivity for the muscarinic M2 receptor subtype. Although the uptake pattern in the biodistribution studies in rats is consistent with muscarinic M2 receptor disribution, specific in vivo binding to these receptors could not be demonstrated. The usefulness of this tracer in human SPET imaging may therefore be limited.