Oral Presentation No.: 014

In vivo characterization in non-human primates of BFEmZIENTand BFEmZBrENT:New serotonin transporter imaging agents: effects of selective

monoamine transporter displacement using microPET

Mark Goodman, J. Stehouwer, N. Jarkas, R. Voll, L. Williams, and J. Votaw

Emory University, Atlanta, GA, USA

Objectives: Considerable evidence derived from the study of postmortem tissue and animal and peripheral cell models of transporter cell

function has convincingly implicated alterations in brain serotonin transporters (SERT) in the pathophysiology of major depression and suicide.

The development of radioligands to map the SERT by positron emission tomography (PET) techniques present unique opportunities to define

the functional status and pharmacology of the SERT in these mood disorders in the living human brain. Carbon-11 labeled 2b-carbomethoxy-

3b-(3V-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT) and 2h-carbomethoxy-3b-(3V-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT)

are novel PET radioligands which bind with high affinity and selectively to cells transfected to express human SERT. mZIENT and mZBrENT

have Ki (nM) = 0.2 vs. [3H]R,S-citalopram and an affinity for the DATand the NET 125- and 165- and 510- and 160-fold lower, respectively.

microPET imaging in monkeys with [11C]mZIENT showed desirable kinetics and high uptake in the midbrain (MB) and thalamus (T),

whereas [11C]mZBrENT showed slower than desirable kinetics for use with carbon-11. The objective of this study was to investigate the

regional uptake, specific binding and binding kinetics of fluorine-18-labeled 2-fluoroethoxy-3b-(3V-((Z)-2-iodoethenyl)phenyl)nortropane-2h-carboxylate (hFEmZIENT) and 2-fluoroethoxy-3b-(3V-((Z)-2-bromoethenyl)phenyl)nortropane-2h-carboxylate (hFEmZBrENT) using

microPET imaging.

Methods and results: hFEmZIENT and hFEmZBrENT were prepared from 2-fluoroethoxy-3h-(3-bromophenylnortropane by treatment with

(Z)-1,2-bis(trimethylstannyl)ethylene followed by ICl and Br2, respectively. In vitro binding studies of hFEmZIENT and hFEmZBrENT in

cells transfected to express human SERT and DAT gave Kis (nM) = 0.4 and 90 and 0.3 and 36, respectively. [18F]hFEmZIENT and

[18F]hFEmZBrENT were prepared in RCY 5 and 3 % respectively by treating their corresponding potassium N-Boc 2h-carboxylateprecursors with NCA 2-[18F]fluoroethylbrosyalte in acetonitrile at 85-C followed by TFA and HPLC purification. The in vivo regional

brain uptakes of [18F]hFEmZIENT and [18F]hFEmZBrENT were determined in anesthetized macaque monkeys after administration of ¨5

mCi using a Concorde microPET P4. [18F]hFEmZIENT and [18F]hFEmZBrENT were administered as a slow (4 min) bolus, and data were

acquired from time of injection until 4 h p.i. Both [18F]hFEmZIENT and [18F]hFEmZBrENT showed high uptake in SERT-rich regions and

displayed favorable kinetics with a peak uptake at 80 min. Displacement studies were carried out by administration of the SERT ligand

citalopram (1.5 mg/kg) 2 h after injection and showed significant washout of the radioactivity from the SERT-rich regions at 4 h post-

injection, proving SERT specificity of these compounds. Finally, displacement studies were also carried out by administration of the

DAT ligand methylphenidate (0.3 mg/kg) 2 h after injection of [18F]hFEmZIENT and [18F]hFEmZBrENT showed insignificant washout

of the radioactivity from brain regions known to be rich in DAT.

Conclusions: This preliminary studies demonstrate that [18F]hFEmZIENT and [18F]hFEmZBrENT administered as a bolus showed fast

kinetics and in vivo specificity, selectivity for CNS SERT and may be a valuable tool for measuring SERT binding in vivo and could be

useful for assessing alterations in brain SERT in the pathophysiology of neuropsychiatric disorders. Future studies planned are for evaluation

in humans.

Research supported by NIMH.

doi:10.1016/j.neuroimage.2006.04.017

ABSTRACTS / NeuroImage 31 (2006) T12–T43 T27