Quantification of [11C]GB67 binding to cardiac α1-adrenoceptors with positron emission tomography: Validation in pigs

So Jin Park-Holohan, Marie Claude Asselin, David R. Turton, Sharron L. Williams, Susan P. Hume, Paolo G. Camici, Ornella E. Rimoldi

Research output: Contribution to journalArticle

Abstract

Introduction: An increase in human cardiac α1-adrenoceptor (α1-AR) density is associated with various diseases such as myocardial ischemia, congestive heart failure, hypertrophic cardiomyopathy and hypertension. Positron emission tomography (PET) with an appropriate radioligand offers the possibility of imaging receptor function in the normal and diseased heart. [11C]GB67, an analogue of prazosin, has been shown in rats to have potential as a PET ligand with high selectivity to α1-AR. However, α1-AR density is up to ten times higher in rat heart compared to that in man. The aim of the present preclinical study was to extend the previous evaluation to a large mammal heart, where the α1- AR density is comparable to man, and to validate a method for quantification before PET studies in man. Methods: Seven [11C]GB67 PET studies, with weight-adjusted target dose of either 5.29 MBq kg-1 (pilot, test-retest and baseline-predose studies) or 8.22 MBq kg-1 (baseline-displacement studies), were performed in four anaesthetised pigs (39.5±3.9 kg). Total myocardial volume of distribution (V T) was estimated under different pharmacological conditions using compartmental analysis with a radiolabelled metabolite-corrected arterial plasma input function. A maximum possible blocking dose of 0.12 μmol kg-1 of unlabeled GB67 was given 20 min before [11C]GB67 administration in the predose study and 45 min after administration of [11C]GB67 in the displacement study. In addition, [15O]CO (3,000 MBq) and [ 15O]H2O, with weight adjusted target dose of 10.57 MBq kg-1, were also administered for estimation of blood volume recovery (RC) of the left ventricular cavity and myocardial perfusion (MBF), respectively. Results: [11C]GB67 V T values (in ml cm -3) were estimated to be 24.2±5.5 (range, 17.3-31.3), 10.1 (predose) and 11.6 (displacement). MBF did not differ within each pig, including between baseline and predose conditions. Predose and displacement studies showed that specific binding of [11C]GB67 to myocardial α1-ARs accounts for approximately 50% of V T. Conclusion: The present study offers a methodology for using [ 11C]GB67 as a radioligand to quantify human myocardial α1-ARs in clinical PET studies.

Original languageEnglish
Pages (from-to)1624-1635
Number of pages12
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume35
Issue number9
DOIs
Publication statusPublished - Sep 2008

Fingerprint

Positron-Emission Tomography
Adrenergic Receptors
Swine
Weights and Measures
Prazosin
Hypertrophic Cardiomyopathy
Carbon Monoxide
Blood Volume
Myocardial Ischemia
Mammals
Heart Diseases
Heart Failure
Perfusion
Pharmacology
Ligands
Hypertension
Amberlite XAD-2 resin

Keywords

  • α-Adrenoceptors
  • [C]GB67
  • Myocardium
  • Pig
  • Positron emission tomography (PET)

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology

Cite this

Quantification of [11C]GB67 binding to cardiac α1-adrenoceptors with positron emission tomography : Validation in pigs. / Park-Holohan, So Jin; Asselin, Marie Claude; Turton, David R.; Williams, Sharron L.; Hume, Susan P.; Camici, Paolo G.; Rimoldi, Ornella E.

In: European Journal of Nuclear Medicine and Molecular Imaging, Vol. 35, No. 9, 09.2008, p. 1624-1635.

Research output: Contribution to journalArticle

Park-Holohan, So Jin ; Asselin, Marie Claude ; Turton, David R. ; Williams, Sharron L. ; Hume, Susan P. ; Camici, Paolo G. ; Rimoldi, Ornella E. / Quantification of [11C]GB67 binding to cardiac α1-adrenoceptors with positron emission tomography : Validation in pigs. In: European Journal of Nuclear Medicine and Molecular Imaging. 2008 ; Vol. 35, No. 9. pp. 1624-1635.
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abstract = "Introduction: An increase in human cardiac α1-adrenoceptor (α1-AR) density is associated with various diseases such as myocardial ischemia, congestive heart failure, hypertrophic cardiomyopathy and hypertension. Positron emission tomography (PET) with an appropriate radioligand offers the possibility of imaging receptor function in the normal and diseased heart. [11C]GB67, an analogue of prazosin, has been shown in rats to have potential as a PET ligand with high selectivity to α1-AR. However, α1-AR density is up to ten times higher in rat heart compared to that in man. The aim of the present preclinical study was to extend the previous evaluation to a large mammal heart, where the α1- AR density is comparable to man, and to validate a method for quantification before PET studies in man. Methods: Seven [11C]GB67 PET studies, with weight-adjusted target dose of either 5.29 MBq kg-1 (pilot, test-retest and baseline-predose studies) or 8.22 MBq kg-1 (baseline-displacement studies), were performed in four anaesthetised pigs (39.5±3.9 kg). Total myocardial volume of distribution (V T) was estimated under different pharmacological conditions using compartmental analysis with a radiolabelled metabolite-corrected arterial plasma input function. A maximum possible blocking dose of 0.12 μmol kg-1 of unlabeled GB67 was given 20 min before [11C]GB67 administration in the predose study and 45 min after administration of [11C]GB67 in the displacement study. In addition, [15O]CO (3,000 MBq) and [ 15O]H2O, with weight adjusted target dose of 10.57 MBq kg-1, were also administered for estimation of blood volume recovery (RC) of the left ventricular cavity and myocardial perfusion (MBF), respectively. Results: [11C]GB67 V T values (in ml cm -3) were estimated to be 24.2±5.5 (range, 17.3-31.3), 10.1 (predose) and 11.6 (displacement). MBF did not differ within each pig, including between baseline and predose conditions. Predose and displacement studies showed that specific binding of [11C]GB67 to myocardial α1-ARs accounts for approximately 50{\%} of V T. Conclusion: The present study offers a methodology for using [ 11C]GB67 as a radioligand to quantify human myocardial α1-ARs in clinical PET studies.",
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T1 - Quantification of [11C]GB67 binding to cardiac α1-adrenoceptors with positron emission tomography

T2 - Validation in pigs

AU - Park-Holohan, So Jin

AU - Asselin, Marie Claude

AU - Turton, David R.

AU - Williams, Sharron L.

AU - Hume, Susan P.

AU - Camici, Paolo G.

AU - Rimoldi, Ornella E.

PY - 2008/9

Y1 - 2008/9

N2 - Introduction: An increase in human cardiac α1-adrenoceptor (α1-AR) density is associated with various diseases such as myocardial ischemia, congestive heart failure, hypertrophic cardiomyopathy and hypertension. Positron emission tomography (PET) with an appropriate radioligand offers the possibility of imaging receptor function in the normal and diseased heart. [11C]GB67, an analogue of prazosin, has been shown in rats to have potential as a PET ligand with high selectivity to α1-AR. However, α1-AR density is up to ten times higher in rat heart compared to that in man. The aim of the present preclinical study was to extend the previous evaluation to a large mammal heart, where the α1- AR density is comparable to man, and to validate a method for quantification before PET studies in man. Methods: Seven [11C]GB67 PET studies, with weight-adjusted target dose of either 5.29 MBq kg-1 (pilot, test-retest and baseline-predose studies) or 8.22 MBq kg-1 (baseline-displacement studies), were performed in four anaesthetised pigs (39.5±3.9 kg). Total myocardial volume of distribution (V T) was estimated under different pharmacological conditions using compartmental analysis with a radiolabelled metabolite-corrected arterial plasma input function. A maximum possible blocking dose of 0.12 μmol kg-1 of unlabeled GB67 was given 20 min before [11C]GB67 administration in the predose study and 45 min after administration of [11C]GB67 in the displacement study. In addition, [15O]CO (3,000 MBq) and [ 15O]H2O, with weight adjusted target dose of 10.57 MBq kg-1, were also administered for estimation of blood volume recovery (RC) of the left ventricular cavity and myocardial perfusion (MBF), respectively. Results: [11C]GB67 V T values (in ml cm -3) were estimated to be 24.2±5.5 (range, 17.3-31.3), 10.1 (predose) and 11.6 (displacement). MBF did not differ within each pig, including between baseline and predose conditions. Predose and displacement studies showed that specific binding of [11C]GB67 to myocardial α1-ARs accounts for approximately 50% of V T. Conclusion: The present study offers a methodology for using [ 11C]GB67 as a radioligand to quantify human myocardial α1-ARs in clinical PET studies.

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