The lead compound of a new series of 3-pyridyl ethers, the azetidine derivative A-85380 (3-[(S)-2-azetidinylmethoxy]pyridine), is a potent and selective ligand for the human alpha4beta2 nicotinic acetylcholine receptor (nAChR) subtype. In vitro, the fluoro derivative of A-85380 (2-fluoro-3-[(S)-2-azetidinylmethoxy]pyridine or F-A-85380) competitively displaced [3H]cytisine or [3H]epibatidine with Ki values of 48 and 46 pM, respectively. F-A-85380 has been labeled with the positron emitter fluorine-18 (t1/2 (half-life) = 110 min) by no-carrier-added nucleophilic aromatic substitution by K[18F]F-K222 complex with (3-[2(S)-N-(tert-butoxycarbonyl)-2-azetidinylmethoxy]pyridin-2-yl) tri methylammonium trifluoromethanesulfonate as a highly efficient labeling precursor, followed by TFA removal of the Boc protective group. The total synthesis time was 50-53 min from the end of cyclotron fluorine-18 production (EOB). Radiochemical yields, with respect to initial [18F]fluoride ion radioactivity, were 68-72% (decay-corrected) and 49-52% (non-decay-corrected), and the specific radioactivities at EOB were 4-7 Ci/micromol (148-259 GBq/micromol). In vivo characterization of [18F]F-A-85380 showed promising properties for PET imaging of central nAChRs. This compound does not bind in vivo to alpha7 nicotinic or 5HT3 receptors. Moreover, its cerebral uptake can be modulated by the synaptic concentration of the endogenous ligand acetylcholine. The preliminary PET experiments in baboons with [18F]F-A-85380 show an accumulation of the radiotracer in the brain within 60 min. In the thalamus, a nAChR-rich area, uptake of radioactivity reached a maximum at 60 min (4% I.D./100 mL of tissue). [18F]F-A-85380 appears to be a suitable radioligand for brain imaging nAChRs with PET.
The reaction [Ru(H2O)6]2+ + L
[Ru(H2O)5L]2+ + H2O was followed as a function of temperature and
ethylene concentration (up to 40 MPa) using a homemade high gas pressure NMR microreactor. The reaction
was first order in H2CCH2 with 103
k
f
298/kg mol-1 s-1 = 1.22 ± 0.06, ΔH
f
⧧/kJ mol-1 = 76.9 ± 2, and ΔS
f
⧧/J
K-1 mol-1 = −42.9 ± 8. These results confirm previous works on mono-complex formation reactions where an
Id mechanism was proposed. The reaction [Ru(H2O)5L]2+ + *L
[Ru(H2O)5*L]2+ + L of exchange of L on
the mono-complex was followed for L = H2CCH2 (103
k
L/kg mol-1 s-1 = 10.8 at 298.2 K), Me2SO (0.35 at
278.5 K), and CO (0.052 at 298.3 K); the rate-determining step is the rupture of the Ru−H2Oax bond with trans-[Ru(H2O)4L2]2+ as reaction intermediate. Due to the trans effect exercised by these strong π-accepting ligands,
the ligand exchange reaction is faster than the mono-complex formation reactions. The cis-bis-complex formation
reaction, [Ru(H2O)5L]2+ + L
cis-[Ru(H2O)4L2]2+ + H2O, was also investigated for L = MeCN (103
k
cis/kg
mol-1 s-1 = 0.111 at 298.1 K), Me2SO (0.019 at 321.6 K), and H2CCH2 (0.007 at 298.1 K, ΔH
cis
⧧/kJ mol-1
= 129.9 ± 4, and ΔS
cis
⧧/J K-1 mol-1 = +92.0 ± 11); here, too, the Ru−H2Oeq bond breaking is rate determining,
but due to the decrease of the lability of water molecules cis to π-accepting ligands, these reactions are much
slower. In the case of MeCN, the reaction scheme includes the formation of the trans-bis-complex and of the
mer-triscomplex. As a general rule, the rate of these complex formation reactions, of dissociative nature, can be
predicted from the oxygen-17 determined water exchange rates.
ABT-418 ((S)-3-methyl-5-[l-methyl-2-pyrrolidinyl]isoxazole) and N-methylcytisine (N-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido-[ I,2-a][ 1,5]diazocin-8-one) are two high affinity nicotinic cholinergic agonists. ABT-418 was synthesized in 7 steps from commercially available (S)-Boc-proline in 35% overall yield. Methylation of commercial cytisine cleanly gave N-methylcytisine. ABT-418 and N-methylcytisine were labelled using ["Cjmethyl iodide by methylation of the corresponding nor-precursors for their in vivo evaluation as positron emission tomography (PET) probes of the nicotinic cholinergic receptors in baboon brain. As for ["Clnicotine, specific binding in vivo could not be demonstrated for ABT-418. Therefore, further experiments are needed to determine the full PET pharmacological profile and the subsequent potential clinical applications of ABT-418 as a tracer for PET experiments. For labelled N-methyl-cytisine, radioactivity in the cerebral cortex and in the blood were similar. Thus, "C-labelled N-methylcytisine does not appear to be a suitable ligand for mapping brain nAChR. E Dolle er a/.
Summary
ABT-418 ((S)-3-methyl-5-[l-methyl-2-pyrrolidinyl]isoxazole)and N-methylcytisine (N-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido-[ I,2-a][ 1,5]diazocin-8-one) are two high affinity nicotinic cholinergic agonists. ABT-418 was synthesized in 7 steps from commercially available (S)-Boc-proline in 35% overall yield. Methylation of commercial cytisine cleanly gave N-methylcytisine. ABT-418 and N-methylcytisine were labelled using ["Cjmethyl iodide by methylation of the corresponding nor-precursors for their in vivo evaluation as positron emission tomography (PET) probes of the nicotinic cholinergic receptors in baboon brain. As for ["Clnicotine, specific binding in vivo could not be demonstrated for ABT-418. Therefore, further experiments are needed to determine the full PET pharmacological profile and the subsequent potential clinical applications of ABT-418 as a tracer for PET experiments. For labelled N-methyl-cytisine, radioactivity in the cerebral cortex and in the blood were similar. Thus, "C-labelled N-methylcytisine does not appear to be a suitable ligand for mapping brain nAChR.
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