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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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S-4-(3-([11C]Isopropylamino)-2-hydroxypropoxy)-2H-benzimidazol-2-one

S-[11C]CGP 12388
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: February 12, 2011.

Chemical name:S-4-(3-([11C]isopropylamino)-2-hydroxypropoxy)-2H-benzimidazol-2-oneimage 8139985 in the ncbi pubchem database
Abbreviated name:S-[11C]CGP 12388
Synonym:S-4-(2-Hydroxy-3-[11C]propan-2-ylamino-propoxy)benzoimidazol-2-one
Agent category:Compound
Target:Peripheral β-adrenoceptors
Target category:Receptor
Method of detection:PET
Source of signal:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Humans
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Changes in β-adrenoceptor (G-protein coupled) density and affinity in the heart, lung and brain have been associated with a variety of disorders, such as myocardial ischemia and infarction, congestive heart failure, asthma, chronic obstructive pulmonary disease, depression, schizophrenia, and Alzheimer’s disease (1-3). There are at least four subtypes of β-adrenoceptor receptors: β1 to β4 (4). Only the β1and β2-subtypes have been studied extensively. The cardiac receptors are found exclusively in the atria and ventricles and are responsible for the regulation of heart rate and myocardial contractility. The human heart and lung have a β1 to β2 ratio of 4:1, and 3:7, respectively. In contrast, the cerebral β-adrenoceptors are heterogeneously distributed in the brain with the highest densities in the caudate and putamen, followed by the cortical areas and thalamus. The brain white matter has low densities. β1-adrenoceptors are found predominately in the putamen and cortex, while the β2-adrenoceptors are found mainly in the hippocampus and cerebellum. The cerebral β-adrenoceptors are implicated in many physiological and behavioral responses.

S-4-(3-(tert-butylamino)-2-hydroxypropoxy)-2H-benzimidazol-one (S-CGP12177) was reported to be an inhibitor of β1- and β2-adrenoceptors (5). S-[11C]CGP 12177 has been studied in vivo by positron emission tomography (PET) producing excellent images of human heart and lung [PubMed]. However, the synthesis of [11C]CGP 12177 was proven to be laborious and often troublesome. Therefore, the isopropyl analogue of S-[11C]CGP 12177, S-4-(3-([11C]isopropylamino)-2-hydroxypropoxy)-2H-benzimidazol-2-one (S-[11C]CGP 12388) is being developed as a PET agent for studying β-adrenoceptors non-invasively in the lung and heart but not the brain since it cannot cross the blood-brain barrier (BBB).

Synthesis

[PubMed]

S-[11C]CGP 12388 was synthesized via a one-pot reaction of 2-[11C]acetone with S-desisopropyl CGP12388 and purified by high-performance liquid chromatography (HPLC) resulted in a radiochemical yield of 18% (end of bombardment) (6). The radiochemical purity was >99.8% with a total synthesis time of 35 min. The specific activity was 22-30 TBq/mmol (600-800 Ci/mmol) at end of synthesis.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In vitro competition binding studies of [3H]CGP 12177 with rat heart membranes produced Kd values of 1.74 and 1.67 nM for CGP12388 and CGP 12177 (7), respectively. Using isolated perfused rat heart model with S-[11C]CGP 12388 kinetic analysis, the Kd values were estimated to be 0.83 ± 0.24 and 1.08 ± 0.31 nM for high-flow group and low-flow group, respectively. Bmax values were 73 ± 15, 4.0 ± 2.0, and 88 ± 14 fmol/mg protein for the high- and low-flow group, respectively. There was no significant difference in Bmax and Kd between the two groups. Pretreatment of hearts with propranolol (a β-adrenoreceptor antagonist) in both groups blocked all S-[11C]CGP 12388 specific binding to the perfused hearts.

Animal Studies

Rodents

[PubMed]

Biodistribution studies in normal rats showed a high accumulation of radioactivity in the lung (10.3% injected dose (ID)/g), followed by the spleen (3.11% ID/g), heart (2.71% ID/g), kidney (1.28% ID/g) and trachea (1.25% ID/g) at 60 min after injection of S-[11C]CGP 12388 (6). There was a low radioactivity (0.07-0.11% ID/g) of the tracer in the brain and plasma. Pretreatment of rats with propranolol decreased significantly the accumulation of S-[11C]CGP 12388 in the heart, spleen and lung. PET studies showed that the lung was clearly visualized and the accumulation was blocked by pretreatment with propranolol. Time-activity curves for the lung indicated that S-[11C]CGP 12388 was slowly washed out (t1/2, 130 min) after a rapid distribution phase. Almost all the radioactivity in the heart and lung was intact S-[11C]CGP 12388 at 60 min post injection (8). The fraction of plasma radioactivity of intact S-[11C]CGP 12388 was 61% at 60 min after injection.

Other Non-Primate Mammals

[PubMed]

No publications are currently available.

Non-Human Primates

[PubMed]

No publications are currently available.

Human Studies

[PubMed]

Elsinga et al (9) reported a human study by administration S-[11C]CGP 12388 to 5 healthy volunteers on two separate days (control and pindolol pretreatment study). Heart, lung and spleen showed high uptake of radioactivity, which was strongly suppressed (68-77%) by pindolol (a β-adrenoceptor antagonist), representing binding to β-adrenoceptors. The washout rates were slow for the heart (0.0056/min), lung (0.0033/min) and spleen (0.015/min). Plasma clearance of S-[11C]CGP 12388 was rapid and tri-phasic (t1/2, 0.22, 2.51 and 101.53 min), binding to plasma proteins was low (53 ± 4%), and S-[11C]CGP12388 was slowly metabolized (87% intact at 10 min). S-[11C]CGP 12388 produced high-quality images of the human thorax.

Doze et al. (10) reported on PET studies in 6 healthy volunteers after three injections of S-[11C]CGP 12388 (high specific activity, low specific activity or unlabeled ligand only). Using tracer kinetic modeling, the Bmax and Kd of S-[11C]CGP 12388 for the β-adrenoceptors in the heart were determined to be 9.74 ± 1.80 nM and 0.58 ± 0.22 nM, assuming a reaction volume of 0.15. Time-activity curves revealed the displacement of S-[11C]CGP 12388 by the unlabeled tracer from the β-adrenoceptors. Using the same kinetic modeling, myocardial β-adrenoceptors was investigated in 6 patients with idiopathic dilated cardiomyopathy and 6 healthy controls using S-[11C]CGP 12388 PET (11). The measured Bmax of the patients (5.4 ± 1.3 pmol/g tissue) decreased 36% (P <0.005) compared to the controls (8.4 ± 1.5 pmol/g tissue).

S-[11C]-CGP12388 in aerosol form was administered to 8 volunteers to inhale the tracer twice, at baseline and after pretreatment with a β-adrenergic drug (salbutamol or pindolol) (12). A dynamic PET scan of the lung was followed by a whole-body scan to assess the inhaled dose at 60 min. Pretreatment consisted either of inhaled salbutamol (a β2-adrenoceptor agonist) (n=4, 400 μg, 20 min before the scan), or orally administered pindolol (a β-adrenoreceptor blocker) (n=4, 3 x 5 mg during a period of 16 h before PET imaging). Drug pretreatment decreased pulmonary accumulation of the radioactivity by only 7%. The agonist salbutamol accelerated the monoexponential washout of radioactivity not only in the peripheral lung (mainly alveoli), but also in the central lung (mainly airways) and in the main bronchi. An even larger increase of the washout rate was induced by the antagonist pindolol. The increased washout rates are the results of the blockade of β-adrenoceptors by salbutamol and pindolol. The washout rate of in the peripheral lung after inhalation (t1/2, 207 ± 48 min) was similar to that observed previously with intravenous injection (t1/2, 218 ± 66 min) (9). Thus, the interaction of drugs with lung β-adrenoceptors can be visualized using PET scanning and an inhaled radioligand.

Internal dosimetry data for S-[11C]CGP 12388 in humans are not available in the literature.

References

1.
Kopka K., Law M.P., Breyholz H.J., Faust A., Holtke C., Riemann B., Schober O., Schafers M., Wagner S. Non-invasive molecular imaging of beta-adrenoceptors in vivo: perspectives for PET-radioligands. Curr Med Chem. 2005;12(18):2057–74. [PubMed: 16101494]
2.
van Waarde A., Vaalburg W., Doze P., Bosker F.J., Elsinga P.H. PET imaging of beta-adrenoceptors in human brain: a realistic goal or a mirage? Curr Pharm Des. 2004;10(13):1519–36. [PubMed: 15134573]
3.
Elsinga P.H., van Waarde A., Vaalburg W. Receptor imaging in the thorax with PET. Eur J Pharmacol. 2004;499(1-2):1–13. [PubMed: 15363946]
4.
Brodde, O.E., Pathophysiology of the beta-adrenoceptor system in chronic heart failure: consequences for treatment with agonists, partial agonists or antagonists? Eur Heart J, 199112 Suppl F: p. 54-62. [PubMed: 1687117]
5.
Affolter H., Hertel C., Jaeggi K., Portenier M., Staehelin M. (-)-S-[3H]CGP-12177 and its use to determine the rate constants of unlabeled beta-adrenergic antagonists. Proc Natl Acad Sci U S A. 1985;82(3):925–9. [PMC free article: PMC397160] [PubMed: 2858094]
6.
Elsinga P.H., van Waarde A., Jaeggi K.A., Schreiber G., Heldoorn M., Vaalburg W. Synthesis and evaluation of (S)-4-(3-(2'-[11C]isopropylamino)-2-hydroxypropoxy) -2H-benzimidazol -2-one ((S)-[11C]CGP 12388) and (S)-4-(3-((1'-[18F]-fluoroisopropyl)amino)-2-hydroxypropoxy) -2H- benzimidazol-2-one ((S)-[18F]fluoro-CGP 12388) for visualization of beta-adrenoceptors with positron emission tomography. J Med Chem. 1997;40(23):3829–35. [PubMed: 9371248]
7.
Momose M., Reder S., Raffel D.M., Watzlowik P., Wester H.J., Nguyen N., Elsinga P.H., Bengel F.M., Remien J., Schwaiger M. Evaluation of cardiac beta-adrenoreceptors in the isolated perfused rat heart using (S)-11C-CGP12388. J Nucl Med. 2004;45(3):471–7. [PubMed: 15001690]
8.
van Waarde A., Elsinga P.H., Doze P., Heldoorn M., Jaeggi K.A., Vaalburg W. A novel beta-adrenoceptor ligand for positron emission tomography: evaluation in experimental animals. Eur J Pharmacol. 1998;343(2-3):289–96. [PubMed: 9570478]
9.
Elsinga P.H., Doze P., van Waarde A., Pieterman R.M., Blanksma P.K., Willemsen A.T., Vaalburg W. Imaging of beta-adrenoceptors in the human thorax using (S)-[(11)C]CGP12388 and positron emission tomography. Eur J Pharmacol. 2001;433(2-3):173–6. [PubMed: 11755150]
10.
Doze P., Elsinga P.H., van Waarde A., Pieterman R.M., Pruim J., Vaalburg W., Willemsen A.T. Quantification of beta-adrenoceptor density in the human heart with (S)-[11C]CGP 12388 and a tracer kinetic model. Eur J Nucl Med Mol Imaging. 2002;29(3):295–304. [PubMed: 12002702]
11.
de Jong R.M., Blanksma P.K., van Waarde A., van Veldhuisen D.J. Measurement of myocardial beta-adrenoceptor density in clinical studies: a role for positron emission tomography? Eur J Nucl Med Mol Imaging. 2002;29(1):88–97. [PubMed: 11807612]
12.
van Waarde A., Maas B., Doze P., Slart R.H., Frijlink H.W., Vaalburg W., Elsinga P.H. Positron emission tomography studies of human airways using an inhaled beta-adrenoceptor antagonist, S-11C-CGP 12388. Chest. 2005;128(4):3020–7. [PubMed: 16236982]

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