Evaluation of [11C]GB67, a novel radioligand for imaging myocardial α1-adrenoceptors with positron emission tomography

Abstract

Dysfunction of the sympathetic nervous system underlies a number of myocardial disorders. Positron emission tomography (PET) offers a way of assessing receptor function non-invasively in humans, but there are no PET radioligands for assessing myocardial alpha-adrenoceptors. GB67, a structural and pharmacological analogue of the alpha 1-adrenoceptor antagonist prazosin, was labelled with positron-emitting carbon-11 (t1/2 = 20.4 min) by 11C-methylation of N-desmethylamido-GB67 (GB99). [11C]GB67 was injected intravenously into conscious rats. Serial arterial blood samples were taken. Rats were killed and tissues removed to determine radioactivity. The percentages of unchanged [11C]GB67 and its radioactive metabolites in plasma and tissues were assessed by HPLC. Plasma clearance of radioactivity was rapid. Myocardial uptake was maximal at 1-2 min and decreased slowly during 60 min. Predosing with adrenoceptor antagonists demonstrated selectivity for myocardial alpha 1-adrenoceptors. GB67 and prazosin blocked uptake of radioactivity; the non-selective antagonist, phentolamine, partially blocked uptake; the alpha 2-adrenoceptor antagonist, RX 821002, only blocked uptake at high dose and the beta-adrenoceptor antagonist, CGP 12177, had no effect. Additionally, injection of prazosin at 20 min after radioligand displaced radioactivity. In vivo competition curves obtained by injecting [11C]GB67 with varying amounts of either unlabelled GB67 or its precursor GB99 were fitted to a competitive binding model to provide estimates of the maximum number of binding sites (Bmax) and half saturation doses (K) for myocardium. Assuming a tissue protein content of 10%, the values of Bmax [approximately 13 pmol.(g tissue)-1[ were similar to those ]50-170 fmol.(mg protein)-1] reported for myocardial alpha 1-adrenoceptors assessed in vitro. Both GB67 and its precursor GB99 had high affinity for alpha 1-adrenoceptors [KGB67 = 1.5 nmol.(kg body weight)-1, KGB99 = 4.8 nmol.(kg body weight)-1]. HPLC demonstrated four radioactive metabolites in plasma. [11C]GB67 was 80% of the radioactivity at 5 min and 50% at 45 min. No radioactive metabolites were detected in myocardium up to 60 min after injection. [11C]GB67 was assessed in two male human volunteers. PET demonstrated high myocardial uptake. The profile of radioactive metabolites in plasma was comparable to that in the rat, although metabolism was slower in humans. Thus, [11C]GB67 is a promising radioligand for assessing alpha 1-adrenoceptors in human myocardium with PET.

Micro-Positron Emission Tomography in the Evaluation of Trypanosoma cruzi-Induced Heart Disease: Comparison with Other Modalities

“…14,15 The PET measures the in vivo body distribution of imaging agents labeled with positron-emitting radionucleotides and has been extensively used in humans to characterize the heart with respect to properties such as perfusion, 16,17 metabolism,18,19 innervation,20,21 and cardiac function. 22,23 With the introduction of high-resolution small-animal PET, 24,25 in vivo molecular imaging of myocardial metabolism in small laboratory animals, mostly mice and rats, has become possible.…”

Preclinical evaluation of an 18F-labelled β1-adrenoceptor selective radioligand based on ICI 89,406

“…Radioligands which have proved useful for studying myocardial neuroreceptors by PET show a decrease in myocardial uptake index as the dose of injected ligand is increased [21,26,30,31]. In vivo dose effect curves for the non-selective β-AR radioligand ( S )-[ 3 H]CGP 12177 have been published for rat myocardium, giving a “ B max ” of 4.7 pmol·(g myocardium) −1 and a “ K D ” of 0.58 nmol·(kg body weight) −1 [21].…”

“…For a subtype selective ligand, the uptake index at low doses would depend on the relative numbers of each subtype. For rat myocardium, 50–80% of β-ARs are of the β 1 -subtype [31–37] from which it might be expected that the uptake index at 0.5 nmol·kg −1 would be 3–4 for the β 1 -subtype and 1–2 for the β 2 -subtype. Uptake indices for ( S )-[ 18 F]F-ICI were 2 for a wide range of doses (Fig.…”

Molecular imaging in heart failure patients

“…Two sequential PET images after an injection of high-specific-activity tracer followed by low-specific-activity tracer allow quantification of β-receptor density using a graphical analysis method [93]. Two other radiolabeled ligands were introduced for adrenoreceptor study: 11 C-CGP 12388 for β-receptor imaging [94], and 11 C GB-67 for α1-receptor imaging [95].

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