title: 3-Pyridyl ethers as SPECT radioligands for imaging nicotinic acetylcholine receptors.
abstract: To develop a suitable single photon emission computed tomography (SPECT) radioligand for neuronal nicotinic acetylcholine receptors (nAChRs) that displays faster in vivo kinetics than 5-[123I]iodo-A-85380, we synthesised the radioiodinated analogue of A-84543. 5-[123I]Iodo-A-84543 was prepared by electrophilic iododestannylation in a modest yield of 23%. In the baboon brain, 5-[123I]iodo-A-85380 displayed a profile consistent with the known distribution of nAChRs, however, 5-[123I]iodo-A-84543 displayed a homogenous uptake with no preferential localisation in regions known to contain nAChRs. To examine the effect of halogen substitution on the 3-pyridyl ether, A-84543, the 5-chloro, 5-bromo and 5-iodo analogues were synthesised and evaluated with respect to nAChR binding. In vitro binding data revealed that halogen substitution at the 5-position of A-84543 was not well tolerated with an increase in halogen size resulting in lower binding towards nAChRs. The 5-chloro analogue 4 displayed highest affinity, Ki =1.3 nM, compared to the 5-bromo and 5-iodo compounds, 5 Ki =3.3 nM and 3 Ki =40.8 nM, respectively. Taken together, these results clearly indicate that 5-[123I]iodo-A-84543 is not suitable for the study of nAChRs in vivo using SPECT.
authors.affiliation: Department of PET and Nuclear Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, Sydney 2050, Australia.
authors.forename: D J
authors.initials: DJ
authors.lastname: Henderson
authors.forename: S
authors.initials: S
authors.lastname: Eberl
authors.forename: S
authors.initials: S
authors.lastname: Thomson
authors.forename: A
authors.initials: A
authors.lastname: Smith
authors.forename: R D
authors.initials: RD
authors.lastname: Allan
authors.forename: M J
authors.initials: MJ
authors.lastname: Fulham
authors.forename: R
authors.initials: R
authors.lastname: Loiacono
authors.forename: M
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D005260:Female; D006847:Hydrocarbons, Iodinated / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes; D008297:Male; D010215:Papio; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011869:Radioligand Assay / Q000379:methods; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000032:analysis* / Q000378:metabolism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
chemical_list: C116733:3-(2-(pyrrolidinyl)methoxy)pyridine; D006847:Hydrocarbons, Iodinated; D007457:Iodine Radioisotopes; D011725:Pyridines; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic