Syntheses of [11C] and [3H] LY274601, a serotonin1A receptor agonist

Abstract

LY274601, R‐(+)‐8‐thiomethyl‐2‐(di‐n‐propylamino)tetralin, a serotonin (5‐HT)1A receptor full agonist with high affinity (Ki: 0.6 nM) and selectivity, was labeled with 11C for imaging 5‐HT1A receptor sites in vivo by positron emission tomography (PET). [11C]LY274601 was synthesized by S‐methylation of the normethyl precursor unmasked via hydrolysis of the butyrate thioester of LY274601. The methylation reaction with [11C]iodomethane proceeded quickly and efficiently in DMF at 40°C, yielding the radiotracer in an average overall radiochemical yield of 35.7±9.8%. The synthesis time including HPLC purification and formulation for injection was approximately 30 min. The specific activity was 630±78 mCi/μmol at the end of synthesis (E.O.S.). This labeling procedure was also employed in the preparation of [3H]LY274601, R‐(+)‐8‐[3H]methylthio‐2‐(di‐n‐propyl‐amino)tetralin, from [3H]iodomethane. © 1998 John Wiley & Sons, Ltd.

A comparison of in vivo and in vitro neuroimaging of 5-HT1A receptor binding sites in the cat brain

“…This approach could give its full meaning to PET defined as ''functional imaging'' of neurotransmitter receptors. Unfortunately, although an abundant literature describes radioligands with in vitro agonist characteristics (Pike et al, 2001, for a review), no attempt to develop a potent 5-HT 1A receptor radioligand agonist in living brain has yet been successful (Mathis et al, 1997;Suehiro et al, 1998). Recently, we evaluated a PET compound presenting a 5-HT 1A receptor agonist activity, which failed to give in vivo receptor-selective signal in rat and in cat brains (Zimmer et al, 2003).…”

A comparison of in vivo and in vitro neuroimaging of 5-HT1A receptor binding sites in the cat brain

“…This approach could give its full meaning to PET defined as ''functional imaging'' of neurotransmitter receptors. Unfortunately, although an abundant literature describes radioligands with in vitro agonist characteristics (Pike et al, 2001, for a review), no attempt to develop a potent 5-HT 1A receptor radioligand agonist in living brain has yet been successful (Mathis et al, 1997;Suehiro et al, 1998). Recently, we evaluated a PET compound presenting a 5-HT 1A receptor agonist activity, which failed to give in vivo receptor-selective signal in rat and in cat brains (Zimmer et al, 2003).…”

Positron Emission Tomography (PET) Imaging Tracers for Serotonin Receptors

“…The R -isomer of 8-SMe-DPAT (named LY274601) was a potent agonist to 5-HT 1A receptors with a high affinity of 0.6 nM ( K i ), which was labeled with 11 C to afford [ 11 C]­LY274601 ([ 11 C] 37 , Figure ). In a biodistribution with mice, [ 11 C] 37 showed high brain uptake and accumulated in receptor-rich regions like the raphe nuclei. Unfortunately, [ 11 C] 37 displayed fast metabolism in vivo and high nonspecific binding by in vitro ARG .…”

A comparison of in vivo and in vitro neuroimaging of 5-HT1A receptor binding sites in the cat brain

“…This approach could give its full meaning to PET defined as ''functional imaging'' of neurotransmitter receptors. Unfortunately, although an abundant literature describes radioligands with in vitro agonist characteristics (Pike et al, 2001, for a review), no attempt to develop a potent 5-HT 1A receptor radioligand agonist in living brain has yet been successful (Mathis et al, 1997;Suehiro et al, 1998). Recently, we evaluated a PET compound presenting a 5-HT 1A receptor agonist activity, which failed to give in vivo receptor-selective signal in rat and in cat brains (Zimmer et al, 2003).…”

Positron Emission Tomography (PET) Imaging Tracers for Serotonin Receptors

“…The R -isomer of 8-SMe-DPAT (named LY274601) was a potent agonist to 5-HT 1A receptors with a high affinity of 0.6 nM ( K i ), which was labeled with 11 C to afford [ 11 C]­LY274601 ([ 11 C] 37 , Figure ). In a biodistribution with mice, [ 11 C] 37 showed high brain uptake and accumulated in receptor-rich regions like the raphe nuclei. Unfortunately, [ 11 C] 37 displayed fast metabolism in vivo and high nonspecific binding by in vitro ARG .…”

A comparison of in vivo and in vitro neuroimaging of 5-HT1A receptor binding sites in the cat brain

“…This approach could give its full meaning to PET defined as ''functional imaging'' of neurotransmitter receptors. Unfortunately, although an abundant literature describes radioligands with in vitro agonist characteristics (Pike et al, 2001, for a review), no attempt to develop a potent 5-HT 1A receptor radioligand agonist in living brain has yet been successful (Mathis et al, 1997;Suehiro et al, 1998). Recently, we evaluated a PET compound presenting a 5-HT 1A receptor agonist activity, which failed to give in vivo receptor-selective signal in rat and in cat brains (Zimmer et al, 2003).…”

Positron Emission Tomography (PET) Imaging Tracers for Serotonin Receptors

“…The R -isomer of 8-SMe-DPAT (named LY274601) was a potent agonist to 5-HT 1A receptors with a high affinity of 0.6 nM ( K i ), which was labeled with 11 C to afford [ 11 C]­LY274601 ([ 11 C] 37 , Figure ). In a biodistribution with mice, [ 11 C] 37 showed high brain uptake and accumulated in receptor-rich regions like the raphe nuclei. Unfortunately, [ 11 C] 37 displayed fast metabolism in vivo and high nonspecific binding by in vitro ARG .…”