A PET-study of [ 11 C]FLB 457 binding to extrastriatal D 2 -dopamine receptors in healthy subjects and antipsychotic drug-treated patients

Abstract

We recently developed [11C]FLB 457 a substituted benzamide with the very high affinity of 20 pM for D2-dopamine receptors in vitro. The aim of the present exploratory study was to examine the anatomical distribution of [11C]FLB 457 binding in the human brain and to determine extrastriatal D2-receptor occupancy in antipsychotic drug-treated patients. [11C]raclopride was used to obtain reference values for D2-dopamine receptor occupancy in the putamen. After IV injection of [11C]FLB 457 there was a high concentration of radioactivity, not only in the caudate putamen but also in the thalamus and the temporal cortex. The concentration of radioactivity in the frontal cortex, the substantia nigra and the colliculi was slightly higher than in the cerebellum. Pretreatment with haloperidol and fluphenazine indicated that [11C]FLB 457 binding in extrastriatal regions to a high degree represent specific binding to D2-dopamine receptors. The D2-occupancy in antipsychotic drug-treated patients was on the same level in the thalamus and the temporal cortex as that determined with [11C]raclopride in the putamen. The study shows that [11C]FLB 457 has potential for quantitative PET-examination of D2-dopamine receptors in man.

Evaluation of Dopamine D-2 Receptor Occupancy by Clozapine, Risperidone, and Haloperidol In Vivo in the Rodent and Nonhuman Primate Brain Using 18F-Fallypride

“…Therefore, this would suggest that in nonhuman primates at a fairly high dose, clozapine interacts with D-2 receptors in all brain regions to a similar extent. Using 11 C-FLB 457, a similar striatal and thalamic occupancy level was reported by Farde et al (1997).…”

“…For equilibrium studies, this region represents the free plus nonspecific radioligand concentration when measuring the bound to free ratios (Farde et al 1997). For kinetic studies, a reference region is used to calculate an index of specific binding, such as binding potential (BP) or distribution volume ratio (DVR) (Fowler et al 1998;Volkow et al 1999).…”

“…A number of studies have investigated the extent of occupancy of the dopamine D-2 receptors in vivo in the striata (caudate and putamen) by various neuroleptics in patients undergoing treatment (summarized recently in Seeman and Tallerico 1999). These studies have been carried out using positron emission tomography (PET with 11 Craclopride and 11 C-FLB 457 as the radioligand; for example, Farde et al 1994Farde et al , 1997Kapur et al 1999) as well as single photon emission tomography (SPECT using 123 I-IBZM and 123 I-epidepride; for example Kufferle et al 1997;Pickar et al 1996;Pilowsky et al 1997). All studies report a high degree of dopamine D-2 receptor occupancy (60 to 90%) by various typical and atypical drugs (Seeman and Tallerico 1999).…”

Positron Emission Tomography Quantification of [11C]-(+)-PHNO Binding in the Human Brain

“…One striking observation of our study was the conspicuously high level of [ 11 C]-( + )-PHNO binding in GP, a region that does not stand out as having a particularly high D 2 -receptor density in vitro and that has been scarcely studied using PET or SPECT. (Farde et al, 1997;Fujita et al, 1999;Mukherjee et al, 2002) but did not report on the visualization of GP in vivo. Only one PET study, using [ 11 C]FLB457 in human, clearly identified GP as a region with high D 2/3 binding, with a binding only slightly less than that measured in caudate-putamen (Okubo et al, 1999).…”

Alterations of Thalamic Activity in Schizophrenia and in Response to Antipsychotic Drugs Studies in the Legacy of Seymour S. Kety

“…The regions showing activation share reciprocal innervation with prefrontal cortex, amygdala and nucleus accumbens, each of which, in turn, are innervated by dopamine and other monoamine neurons (Groenwegen 1988;Su and Bentivoglio 1990;Vogt et al 1993;Lavin and Grace 1998). However, the thalamus, too, in human as in rat, shows evidence of dopamine and other monoamine innervation (Nieuwenhuys et al 1988;Farde et al 1997). Thus the effects observed may well be direct ones.…”