Positron-emitting radioligands for imaging neuroleptic receptors Page: 1 of 2
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POSITION-EMITTING BADIOLICAMDS IOE IMAGING MtUEOLERXC IECEPTOM.
Carroll D. Arnett, Joanna S. fowler, *4if red P. Volf, Chyiflam Shloa, and
Joan Logan, Chemistry Department, Brookhaven National Laboratory, Upton, R
11973 USA
A aariaa of *®P-labeled butyrophanona naurolaptiea was evaluated in
baboons and rats with rsspact to potantlal utility as radioligands for
studying naurolaptic racaptors in tha living human brain by positron
aalssion tonography (PET). Tha sarias ineludad banparidol, haloparldol, §
apiroparidol, and N-methylspiroperidol. Tha eritaria nsad for tha aralus- g
tion wars: 1) a rapid radiochemical synthasls and purification, 2) a high a
specific activity product, 3) a rapid and significant brain panatratiou, g§ §
A) nlninal radioactive metabolites within tha brain during tha scanning « £
period, 5) a high dagrsa of specificity of receptor binding, and 6) a 8 2
relatively slow in vivo dissociation froa the receptor once bound (1). £
Tha first two criteria ware net for all four coapounds with the develop-
ment of a general ayntheaia (2) for butyrophanones radiolabeled with
fluorine-18 to specific activities greater than 10 Ci/pnol, calculated to
tha and of cyclotron bombardnent (3). These compounds were administered to
baboons, and the radioactivity distributions to the striatum, a region of
high receptor concentration, and to the cerebellum, a region of low receptor
concentration, ware determined by PET at various tines up to 8 hours after
laotope injection (1,4). Stereospecific binding to neuroleptic receptors
was demonstrated in the striatum but not in the cerebellum by comparing
studies in the same animal pretreated with either (-)- or (+)-butaclamol.
Among the radioligands studied, [ ]benperidol, [^®P]spiroperidol, and
[ 1®F ]-N-*ethylspiroperidol exhibited appropriate in vivo stereospedflc
binding kinetics to be useful for studying .neuroleptic receptors. Analysis
of baboon blood for radioactive metabolites indicates a rapid peripheral
metabolism for these compounds. However, the very long retention of
radioactivity in the striatum suggests that very little metabolism tekes
place in the central, nervous system. Analysis of rat brain at
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ism takes |«
after injection of [^*7]spiroperidol or [*®71-I*«ethylsplroperldol
strated that greater than 952 of the radioactivity In the strlat
to unchanged radioligand for as long as 4 hours after injection. The
absolute striatal uptake (in percent of administered dose) in the baboon wms
at least two-fold higher for [*®7]-N-methylspiroperidol than for spiro-
peridol. In the rat, the striatal uptake wms five-fold higher for the
H-methyl radioligand.
Although [*®7]haloperidol exhibited a higher initial brain uptake than
the other three, the distribution of radioactivity wms predominantly to
nonspecific sites, and the striatal retention was much less than for the
other coapounds. [l*7]Benperldol, I1®!]spiroperidol, and [*®7]-N-methyl-
splroperldol all showed a high percentaga of specifically bound component of
radioactivity in the baboon striatum which Increased for the duration of the
study. At 4 hours after injection, the striatum to cerebellum ratios for
these three compounds were 7.3, 3.4, and 8.0, respectively, whereas for
[^■^Fjhaloperidol the corresponding ratio was 1.6. [*®7]Spiroperidol
exhibited a higher initial distribution to cortical areas than either
l1®F]benperidol or [18F]-H-methylspiroperidol, suggesting a lower speci-
ficity with perhaps a higher proportion of binding to serotonin receptors in
these regions, as has bean found for [®H]splroperldol. These results
indicate that [187]-N-methylspiroperidol, because of its high brain uptake,
o of m tmmorr is mumib
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Arnett, C. D.; Fowler, J. S.; Wolf, A. P.; Shiue, C. Y. & Logan, J. Positron-emitting radioligands for imaging neuroleptic receptors, article, January 1, 1985; Upton, New York. (https://digital.library.unt.edu/ark:/67531/metadc1069861/m1/1/: accessed July 16, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.