In vivo SPECT imaging of 5-HT1A receptors with [123I]p-MPPI in nonhuman primates

Abstract

The in vivo imaging of a novel iodinated phenylpiperazine derivative for 5-HT1A receptors, [123I]p-MPPI (4-(2'-methoxy-)phenyl-1-[2'-(n-2"-pyridinyl)-p-iodobenzamido-] ethyl-piperazine), using single photon emission computed tomography (SPECT), was evaluated in nonhuman primates. After an i.v. injection, [123I]p-MPPI penetrated the blood-brain barrier quickly and localized in brain regions where 5-HT1A receptor density is high (hippocampus, frontal cortex, cingulate gyrus, entorhinal cortex). Maximum ratio of hippocampus to cerebellum was 3 to 1 at 50 min postinjection. The specific binding of the radioligand in the hippocampal region, an area rich in 5-HT1A receptor density, was blocked by a chasing dose of (+/-) 8-OH-DPAT (2 mg/kg, i.v.) or non-radioactive p-MPPI (1 mg/kg, i.v.), whereas the regional distribution of [123I]p-MPPI was unaffected by treatment with non 5-HT1A agents, such as ketanserin. Ex vivo and in vitro autoradiographic studies using monkey brain further confirmed that the specific binding of [123I]p-MPPI is associated with 5-HT1A receptor sites. However, the initial attempt at [123I]p-MPPI human imaging studies did not display specific localization of 5-HT1A receptors. This discrepancy observed for [123I]p-MPPI may be due to a dramatic difference in metabolic pathways between humans and monkeys.

5‐HT radioligands for human brain imaging with PET and SPECT

“…A similar profile was seen in the nonhuman primate brain, suggesting [ 123 I] p ‐MPPI could prove useful as a SPECT radioligand. Specific binding could be blocked by pretreatment with 8‐OH‐DPAT or WAY‐100635, as is seen both in ex vivo and in vitro autoradiographic studies . By contrast, [ 123 I] p ‐MPPI did not display specific localization to 5‐HT 1A receptor‐rich brain areas in humans.…”

Differential discrimination of G‐protein coupling of serotonin1A receptors from bovine hippocampus by an agonist and an antagonist

“…OH‐DPAT) have been discovered more than a decade ago [17], the development of selective 5‐HT 1A antagonists has been relatively slow and less successful. Recently, p ‐MPPI and p ‐MPPF have been introduced as selective antagonists for the 5‐HT 1A receptor [19–22]. These compounds bind specifically to 5‐HT 1A receptor with a high affinity.…”

The spleen is required for 5-HT1Areceptor agonist-mediated increases in mean circulatory filling pressure during hemorrhagic shock in the rat

“…Previously we showed that low-dose 8-OH-DPAT (1 g) produced a robust and rapid sympathoexcitatory effect in hemorrhaged rats when administered into the cisterna magna, while the same dose of drug had no effect when given systemically (34). 8-OH-DPAT readily crosses the blood-brain barrier and has significant agonist activity at 5-HT 1A and 5-HT 7 serotonergic receptors (4,19). Our earlier work also showed that the selective 5-HT 1A receptor antagonist WAY100635 dose dependently reversed the ability of centrally administered 8-OH-DPAT to maintain blood pressure during hemorrhage (35).…”