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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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(R)-(-)-2-Chloro-N-[1-11C-propyl]n-propylnorapomorphine

2-Cl-[11C]-(-)-NPA
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: December 11, 2010.

Chemical name:(R)-(-)-2-Chloro-N-[1-11C-propyl]n-propylnorapomorphineimage 99430929 in the ncbi pubchem database
Abbreviated name:2-Cl-[11C]-(-)-NPA
Synonym:
Agent category:Compound
Target:D3 dopamine receptors
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure for additional information in PubChem.

Background

[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 through D5, have been well characterized pharmacologically and biochemically (4). These five subtypes are classified into two subfamilies: D1-like (D1 and D5) and D2-like (D2, D3, and D4) dopamine receptors. D1-Like and D2-like receptors exert synergistic as well as opposite effects at both the biochemical and overall system levels. A great majority of striatal D1 and D2 receptors are localized postsynaptically on caudate-putamen neurons and to a lesser extent presynaptically on nigrostriatal axons.

Dopamine receptors are G-protein–coupled receptors and exist in high- and low-affinity states with respect to agonist binding. The two states are interconvertible. The high-affinity state is coupled to G-proteins, whereas the low-affinity state is not. Dopamine has a dissociation constant (Kd) of 7 nM for the high-affinity state (Khigh) and a Kd of 1,720 nM for the low-affinity state (Klow) (5). Under physiological conditions, dopamine is expected to bind predominantly to the high-affinity state, which is ~50% occupied by 10 nM dopamine. The high-affinity state was suggested to be the functional form of the dopamine receptors.

Substituted benzamides, such as sulpiride, raclopride, and iodobenzamide, are specific ligands with only moderate affinity for the D2-like receptors, making studies of extrastriatal D2 receptors difficult (6-8). In binding studies, 123I-labeled epidepride, an analog of isoremoxipride, was found to have high potency and low nonspecific binding, and to be selective for striatal and extrastriatal D2 receptors (9). Epidepride has marginal binding to D4 receptors, with little affinity for other known neurotransmitter receptors. (S)-N-((1-Allyl-2-pyrrolidinyl)methyl)-5-(3-[18F]fluoropropyl)-2,3-dimethoxybenzamide ([18F]fallypride), an analog of epidepride, was found to be a selective, high-affinity antagonist of D2/3 receptors (10) in positron emission tomography (PET) in vivo studies (11-13). [18F]fallypride identified extrastriatal D2/3 receptors. However, none of these antagonists distinguish between the high- and low-affinity states of the D2 receptors. (-)-N-Propyl-norapomorphine (NPA) was reported to have Khigh and Klow values of 0.07–0.4 and 20–200 nM, respectively (5, 14-16). This provides a >50-fold selectivity for the high-affinity over the low-affinity receptors. NPA has good affinity (Ki, 0.3 nM) for D3 receptors but not other neurotransmitters (17). [11C]NPA is being developed as a PET agent for the noninvasive study of the high-affinity state of the D2 receptors in the brain. (R)-(-)-2-Chloro-N-[1-11C-propyl]n-propylnorapomorphine (2-Cl-[11C]-(-)-NPA) has been evaluated as a D3-selective probe because 2-Cl-(-)-NPA showed a higher selectivity for D3 than for D2 (D3/D2, 3.85) than did (-)-NPA (D3/D2, 1.75) (18).

Synthesis

[PubMed]

Palner et al. (18) reported a one-pot synthesis of 2-Cl-[11C]-(-)-NPA by reacting [11C]propionyl chloride with (-)-chloronorapomorphine hydrobromide and a LiAlH4 reduction, with a radiochemical yield of ~9% (based on [11C]CO2, end of bombardment) and specific activities of 28–45 GBq/μmol (757–1,220 mCi/μmol) at the end of synthesis after C-18 Sep-Pak and purification with high-performance liquid chromatography. Radiochemical purities were >97%. [11C]Propionyl chloride was prepared by reacting [11C]CO2 with ethylmagnesium bromide, followed by reaction with phthaloyl chloride. The total synthesis time was ~40 min.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In binding to dopamine receptors in membranes of porcine anterior pituitary, [3H]NPA had an average Kd of 0.26 ± 0.01 nM and a Bmax of 2.3 ± 0.1 pmol/g tissue (19). 2-Cl-[11C]-(-)-NPA exhibited Ki values of 4.52 ± 0.98 and 17.26 ± 2.88 nM for D2 and D3, respectively (18). [11C]-(-)-NPA had Ki values of 0.12 ± 0.04 and 0.21 ± 0.09 nM for D2 and D3, respectively. The cLog D values were calculated to be 2.25 and 0.79 for 2-Cl-[11C]-(-)-NPA and [11C]-(-)-NPA, respectively.

Animal Studies

Rodents

[PubMed]

Palner et al. (18) performed ex vivo brain biodistribution studies of 37 MBq (1 mCi) 2-Cl-[11C]-(-)-NPA in rats. 2-Cl-[11C]-(-)-NPA accumulated more slowly in the striatum than did [11C]-(-)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[11C]-(-)-NPA (standard uptake value (SUV) = 0.72 ± 0.24) was approximately half that of [11C]-(-)-NPA (SUV = 1.37 ± 0.18). Nonspecific uptake was similar for the two tracers in the cerebellum (SUV = 0.32–0.33). The striatum/cerebellum ratios were 1.18 and 3.31 for 2-Cl-[11C]-(-)-NPA and [11C]-(-)-NPA, respectively, at 60 min after injection. 2-Cl-[11C]-(-)-NPA was metabolized quickly to one major and two minor less lipophilic metabolites, leaving only 17% of 2-Cl-[11C]-(-)-NPA in the plasma after 30 min. The specific binding of 2-Cl-[11C]-(-)-NPA was completely blocked by pretreatment with haloperidol (5 mg/kg, 30 min). The authors concluded that 2-Cl-[11C]-(-)-NPA is less likely to be more useful as a PET agent than [11C]-(-)-NPA because of slower brain uptake and a lower striatum/cerebellum ratio.

Other Non-Primate Mammals

[PubMed]

No publications are currently available.

Non-Human Primates

[PubMed]

No publications are currently available.

Human Studies

[PubMed]

No publications are currently available.

NIH Support

N01MH32004

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