Radioiodinated SB 207710 as a radioligand in vivo: imaging of brain 5-HT4 receptors with SPET.
Single-photon emission tomography (SPET) and positron emission tomography (PET), when coupled to suitable radioligands, are uniquely powerful for investigating the status of neurotransmitter receptors in vivo. The serotonin subtype-4 (5-HT(4)) receptor has discrete and very similar distributions in rodent and primate brain. This receptor population may play a role in normal cognition and memory and is perhaps perturbed in some neuropsychiatric disorders. SB 207710 [(1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate] is a selective high-affinity antagonist at 5-HT(4) receptors. We explored radioiodinated SB 207710 as a possible radioligand for imaging 5-HT(4) receptors in vivo. Rats were injected intravenously with iodine-125 labelled SB 207710, euthanised at known times and dissected to establish radioactivity content in brain tissues. Radioactivity entered brain but cleared rapidly and to a high extent from blood and plasma. Between 45 and 75 min after injection, the ratios of radioactivity concentration in each of 12 selected brain tissues to that in receptor-poor cerebellum correlated with previous measures of 5-HT(4) receptor density distribution in vitro. The highest ratio was about 3.4 in striatum. SB 207710 was labelled with iodine-123 by an iododestannylation procedure. A cynomolgus monkey was injected intravenously with [(123)I]SB 207710 and examined by SPET. Maximal whole brain uptake of radioactivity was 2.3% of the injected dose at 18 min after radioligand injection. Brain images acquired between 9 and 90 min showed high radioactivity uptake in 5-HT(4) receptor-rich regions, such as striatum, and low uptake in receptor-poor cerebellum. At 169 min the ratio of radioactivity concentration in striatum to that in cerebellum was 4.0. In a second SPET experiment, the cynomolgus monkey was pretreated with a selective 5-HT(4) receptor antagonist, SB 204070, at 20 min before [(123)I]SB 207710 injection. Radioactivity in all brain regions was reduced almost to the level in cerebellum by 176 min after radioligand injection. These findings show that [(123)I]SB 207710 is an effective radioligand for imaging brain 5-HT(4) receptors in vivo.
MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, W12 0NN, London, UK. victor.pike@nih.gov
Victor W
VW
Pike
Christer
C
Halldin
Kenji
K
Nobuhara
Julka
J
Hiltunen
Rachel S
RS
Mulligan
Carl-Gunnar
CG
Swahn
Per
P
Karlsson
Hans
H
Olsson
Susan P
SP
Hume
Ella
E
Hirani
Jaqueline
J
Whalley
Lyn S
LS
Pilowsky
Stig
S
Larsson
Per-Olof
PO
Schnell
Peter J
PJ
Ell
Lars
L
Farde
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004146:Dioxanes / Q000097:blood / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes / Q000097:blood / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D013045:Species Specificity; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
D004146:Dioxanes; D007457:Iodine Radioisotopes; D008024:Ligands; D010880:Piperidines; D019275:Radiopharmaceuticals; C088873:SB 207710; D044422:Receptors, Serotonin, 5-HT4