[PubMed]

Dopamine, a neurotransmitter, plays an important role in the mediation of movement, cognition, and emotion (1, 2). Dopamine receptors are involved in the pathophysiology of neuropsychiatric diseases, such as Parkinson’s disease, Alzheimer's disease, Huntington’s disease, and schizophrenia (3). Five subtypes of dopamine receptors, D₁-₅, were well-characterized pharmacologically and biochemically (4). These five subtypes were classified into two subfamilies of D₁-like (D₁, D₅) and D₂-like (D₂, D₃, D₄) dopamine receptors. D₁-like and D₂-like receptors exert synergistic as well as opposite effects at the biochemical and overall system levels. A great majority of striatal D₁ and D₂ receptors are localized postsynaptically on the caudate-putamen neurons and to a lesser extent presynaptically on nigrostiatal axons.

(R)-(+)-8-Chloro-2,3,4,5-tetrahydro-3-[¹¹C]methyl-5-phenyl-1H-3-benzazepin-7-ol ([¹¹C]SCH 23390) was found to be a selective, high-affinity antagonist of D₁ receptors. SCH 23390 was found to have marginal effect on D₂, α₁-adrenergic, muscarinic and histaminergic receptors and only a slight effect on 5-HT_2A receptors (5). [¹¹C]SCH 23390 positron emission tomography (PET) has been used to study D₁ receptor occupancy and density in neuropsychiatric disorders and aging in humans.

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[PubMed]

[¹¹C]SCH 23390, was synthesized by alkylation of the desmethyl compound SCH 24518 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro-5-phenyl-1H-3-benzazepin-7-ol) with [¹¹C]methyl iodide (6). Reaction in acetone with subsequent normal-phase LC separation resulted in 80% radiochemical yield, based on [¹¹C]methyl iodide, with a total synthesis time of 35-40 min and a radiochemical purity greater than 99%. The averaged specific activity was 11.1 GBq/mmol (300 Ci/mmol) at end of synthesis (EOS).

[PubMed]

SCH 23390 was reported to have selective binding affinity to D₁ (striatum) and 5-HT_2A (frontal cortex) receptor sites in homogenates of rat brain membranes (7). The K_i values for D₁ ([³H]piflutixol), D₂ ([³H]spiroperidol) in the striatal membranes and 5-HT_2A ([³H]spiroperidol) in the cortical membranes were 1.3 nM, 880 nM and 30 nM, respectively. It has a K_i value of 690 nM for the α₁-adrenergic receptor in rat forebrain membrane. The affinity for the 5-HT_2A receptor is about 10-fold lower than that for the D₁ receptor, suggesting that specific [¹¹C]SCH 23390 binding visualized by PET represents mainly binding to D₁ receptors. The K_d value of [³H]SCH 23390 was 0.53 nM for D₁(8). The B_max value of [³H]SCH 23390 for D₁ was 69 pmol/g tissue.

Using human putamen homogenates, the K_d values of [³H]SCH 23390 and [³H]raclopride, a D₂ antagonist, were 1.6 ± 0.22 nM (1.1 ± 0.38 nM with 40 nM ketanserin, a 5-HT_2A antagonist) and 2.0 ± 0.2 nM, respectively (9). The D₁ receptor binding density (B_max) was 12.7 ± 3.8 and 9.9 ± 2.1 pmol/g tissue for [³H]SCH 23390 without and with 40 nM ketanserin, respectively. The B_max of [³H]raclopride for D_2/3 receptor was 13.3 ± 0.9 pmol/g tissue. Using frontal cortex membranes, the B_max for D₁ was 6.7 ± 3.9 and 3.3 ± 0.82 pmol/g tissue without and with 40 nM ketanserin, respectively. Ketanserin had little effect on the K_d (2.1 - 2.4 nM). There was little specific binding of raclopride in the cortex membranes. Therefore, part of the [³H]SCH 23390 bindings to the putamen and frontal cortex was due to 5-HT_2a receptor sites.

Hyttel (10) reported that the B_max and K_d of dopamine D₁ and D₂ receptors in striatum was estimated in rats of different ages (from 3.5 to 25 months) using [³H]SCH 23390 and [³H]spiperone as ligands. The density of D₁ and D₂ receptors decreased with age from 3.5 months’ values of 990 ± 50 and 350 ± 11 pmol/g tissue to 25 months’ values of 690 ± 35 (30% decrease) and 240 ± 7 pmol/g tissue (31% decrease), respectively. However, the K_d vaukes remained constant. The decreases in density of D₁ and D₂ receptors were parallel. Thus, the ratio between the density of D₁ and D₂ receptors remained constant throughout life

Hess et al (11) demonstrated that D₁ receptor density ([³H]SCH 233900) was reduced by 43% in postmortem caudate brains from 8 schizophrenic patients as compared with 8 normal subjects from 281.5 ± 20.5 to 161.4 ± 22.1 fmol/mg protein. In contrast, schizophrenic patients exhibited a 56% increase in D₂ receptor density from 119.8 ± 13.7 to 186.7 ± 33.0 fmol/mg protein as measured by [³H]spiperone in the presence of 40 nM ketanserin. These resulted in a highly significant difference in the ratio of D₂/D₁ receptor density between schizophrenic patients (1.29 ± 0.29) and controls (0.42 ± 0.03).

[PubMed]

[¹¹C]SCH 23390 PET studies of D₁ receptor distribution in human brain were reported, showing a major localization of radioactivity in the striatum. Striatum-to-cerebellum ratio and kinetic constants are commonly used as analytical parameters in [¹¹C]SCH 23390 PET studies with good reproducibility (14-16). Farde et al. (17) reported on [¹¹C]SCH 23390 PET studies in 2 patients with schizophrenia and in 3 normal subjects. PET brain scans of normal subjects showed that a high accumulation of radioactivity was in the putamen, followed by the neocortex and cerebellum at 5 - 60 min after injection of 100 MBq (2.7 mCi) [¹¹C]SCH 23390. The putamen-to-cerebellum ratio was 3 at 25 min. There was a marked accumulation of radioactivity in the neocortex for [¹¹C]SCH 23390 but not for [¹¹C]raclopride (D_2/3 receptors), suggesting the presence of 5-HT_2A binding sites. Only about 1.2% of injected [¹¹C]SCH 23390 remained in the brain at 4.5 min. Only 15% of radioactivity remained intact in blood at 42 min. PET scans of schizophrenic patients was similar to those obtained in the normal controls. [¹¹C]SCH 23390 PET was able to assess striatal dopamine receptor occupancies in patients treated with various antipsychotic drugs (18).

The effects of age on the binding of [¹¹C]SCH 23390 for D₁ receptor sites were studied in 17 healthy male subjects in age from 20 to 72 years old (19). The binding potential of the D₁ receptors in the striatum and frontal cortex decreased with age by 35% and 39%, respectively. In another study with 8 men and 10 women (22-74 years old) (20), there was an age dependent decrease of D₁ receptor binding potential in the caudate, putamen, and occipital cortex by 6.9%/decade, 7.4%/decade, and 8.6%/decade, respectively. There was no difference in D₁ binding potentials between men and women.

In Huntington’s disease, there was a significant reduction in both the D₁ ([¹¹C]SCH 23390) and D₂ ([¹¹C]raclopride) binding potentials in the striatum (21-23). A great majority (90%) of patients was not on any medication affecting the dopamine and serotonin system. Medications were withdrawn for 1 to 14 days prior to PET. In Parkinson’s disease, there was no significant difference in D₁ receptor accumulation in the pathologic striatum compared with the contralateral striatum (24). On the other hand, there was a significant increase in D₂ binding potential in the striatum contralateral to the symptoms as compared with the opposite striatum. None of the patients was on any anti-Parkinsonism medication.

Kosaka et al. performed [¹¹C]NNC112 and [¹¹C]SCH23390 PET imaging in six patients with schizophrenia in severe residual phase with chronic antipsychotic treatment and twelve healthy age-matched controls on the same subjects. The D₁ binding potential (BP_ND)values of both tracers in the frontal cortex, anterior cingulate, temporal cortex and striatum of the patients were significantly lower (21-31%) than those of the healthy controls (P < 0.001).

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[¹¹C]SCH 23390 PET is useful for objective monitoring of D₁ receptor density and drug occupancy in patients with dopaminergic disorders. Internal dosimetry data for [¹¹C]SCH 23390 in humans are not available in the literature.

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