Number Of Radioligands Research Articles

Molecular imaging in nuclear cardiology: Pathways to individual precision medicine

Growth of molecular imaging bears potential to transform nuclear cardiology from a primarily diagnostic method to a precision medicine tool. Molecular targets amenable for imaging and therapeutic intervention are particularly promising to facilitate risk stratification, patient selection and exquisite guidance of novel therapies, and interrogation of systems-based interorgan communication. Non-invasive visualization of pathobiology provides valuable insights into the progression of disease and response to treatment. Specifically, inflammation, fibrosis, and neurohormonal signaling, central to the progression of cardiovascular disease and emerging therapeutic strategies, have been investigated by molecular imaging. As the number of radioligands grows, careful investigation of the binding properties and added-value of imaging should be prioritized to identify high-potential probes and facilitate translation to clinical applications. In this review, we discuss the current state of molecular imaging in cardiovascular medicine, and the challenges and opportunities ahead for cardiovascular molecular imaging to navigate the path from diagnosis to prognosis to personalized medicine.

Autoradiographic localisation of [ 3H]2-BFI imidazoline I 2 binding sites in mouse brain

Imidazoline I 2 binding sites are heterogeneous in nature and have been observed in the brain of a number of species. Development of specific imidazoline I 2 radioligands, such as [ 3H]2-BFI and [ 3H]BU224, that have a high affinity for the imidazoline I 2 binding site, has enabled the central distribution of these sites to be mapped. Extensive studies have been conducted on the rat brain with a number of radioligands. However, to date a comprehensive analysis of imidazoline I 2 ligand binding in mouse brain has not been completed. In the present work we describe levels of [ 3H]2-BFI specific binding found throughout the mouse brain. [ 3H]2-BFI (2 nM) showed discrete regional distribution which was readily displaced by saturating concentrations of the specific imidazoline I 2 ligand BU224. The highest levels of [ 3H]2-BFI specific binding were found in the dorsal raphe, paraventricular thalamus and nucleus accumbens. Moderate levels were found throughout the lining of the aqueduct, lateral ventricle, lateral 4th ventricle, 4th ventricle, 3rd ventricle, but not the dorsal 3rd ventricle. Based on the loss of [ 3H]idazoxan binding in brain homogenates from monoamine oxidase-A and B (MAO-A and MAO-B) deficient mice it has been suggested that imidazoline I 2 binding sites are predominantly on MAO. Consistent with this hypothesis the regional distribution of [ 3H]2-BFI shows some overlap with that previously reported for MAO. However, in the rat imidazoline I 2 binding sites have been shown to be heterogeneous in nature and it is likely [ 3H]2-BFI is binding to multiple imidazoline I 2 binding sites within mouse brain.

Radioligands for imaging myocardial alpha- and beta-adrenoceptors.

Alpha- and beta-adrenoceptors play an important role in the control of heart function. According to their molecular, biological, and pharmacological characteristics, they are subdivided into alpha(1)-, alpha(2)- and beta(1)-, beta(2)-, beta(3)-, beta(4)-adrenoceptors. In cardiac disease, there is often a selective downregulation of beta(1)-adrenoceptors associated with a relative increase in beta(2)- and alpha(1)-adrenoceptors. Functional imaging techniques like single-photon emission tomography (SPECT) and positron emission tomography (PET) provide the unique capability for non-invasive assessment of cardiac adrenoceptors. Radioligands with high specific binding to cardiac alpha- and beta-adrenoceptors suitable for radiolabelling are required for clinical studies. The non-selective beta-adrenoceptor antagonist [(11)C]CGP-12177 was used to quantify beta-adrenoceptor density using PET in patients with heart disease. New non-selective ligands (e. g. [(11)C]CGP-12388, [(18)F]CGP-12388, [(11)C]carazolol and [(18)F]fluorocarazolol) are currently evaluated; beta(1)-selective radioligands (e. g. [(11)C]CGP-26505, [(11)C]bisoprolol, [(11)C]HX-CH 44) and beta(2)-selective radioligands (e. g. [(11)C]formoterol, [(11)C]ICI-118551) were assessed in animals. None of them turned out as suitable for cardiac PET. Potential radioligands for imaging cardiac alpha(1)-adrenoceptors are based on prazosin. Whereas [(11)C]prazosin shows low specific binding to myocardium, its derivative [(11)C]GB67 looks more promising. The putative alpha(2)-adrenoceptor radioligand [(11)C]MK-912 shows high uptake in rodent myocardium but has not yet been evaluated in man. A number of radioligands were evaluated for assessing cardiac adrenoceptors using PET. New radioligands are needed to provide more insight into cardiac pathophysiology which may influence the therapeutic management of patients with cardiovascular disease.

Radioligands for imaging myocardial α- and β-adrenoceptors

SummaryAlpha- and beta-adrenoceptors play an important role in the control of heart function. According to their molecular, biological, and pharmacological characteristics, they are subdivided into α1-, α2- and β1-, β2-, β3-, β4-adrenoceptors. In cardiac disease, there is often a selective downregulation of β1-adrenoceptors associated with a relative increase in β2- and α1-adrenoceptors. Functional imaging techniques like single-photon emission tomography (SPECT) and positron emission tomography (PET) provide the unique capability for non-invasive assessment of cardiac adrenoceptors. Radioligands with high specific binding to cardiac α- and β-adrenoceptors suitable for radiolabelling are required for clinical studies. The non-selective β-adrenoceptor antagonist [11C]CGP-12177 was used to quantify β-adrenoceptor density using PET in patients with heart disease. New non-selective ligands (e. g. [11C]CGP-12388, [18F]CGP-12388, [11C]carazolol and [18F]fluorocarazolol) are currently evaluated; β1-selective radioligands (e. g. [11C]CGP-26505, [11C]bisoprolol, [11C]HX-CH 44) and β2-selective radioligands (e. g. [11C]formoterol, [11C]ICI-118551) were assessed in animals. None of them turned out as suitable for cardiac PET.Potential radioligands for imaging cardiac α1-adrenoceptors are based on prazosin. Whereas [11C]prazosin shows low specific binding to myocardium, its derivative [11C]GB67 looks more promising. The putative α2-adrenoceptor radioligand [11C]MK-912 shows high uptake in rodent myocardium but has not yet been evaluated in man.A number of radioligands were evaluated for assessing cardiac adrenoceptors using PET. New radioligands are needed to provide more insight into cardiac pathophysiology which may influence the therapeutic management of patients with cardiovascular disease.

Chapter 5 Mapping of brain nicotinic receptors by autoradiographic techniques and the effect of experimental lesions

Publisher Summary This chapter discusses mapping of brain nicotinic receptors by autoradiographic techniques and the effect of experimental lesions. Nicotinic binding sites have been detected using a number of radioligands in in vitro assays of mammalian brain. The most commonly used radioligands are [ 3 H]nicotine, [ 3 H]acetylcholine and 125 I-labelled-α-bungarotoxin. All three bind with high affinity in a saturable and reversible manner, inhibited selectively by nicotinic agents. A much greater degree of neuroanatomical detail can be achieved with receptor autoradiography. High-affinity nicotinic binding sites for [ 3 H]nicotine, [ 3 H]ACh, and to a lesser extent [ 3 H]methylcarbachol have all been mapped autoradiographically in rat brain with virtually identical results. Dense autoradiographic labelling is observed in the medial habenula and interpeduncular nucleus; in the so-called specific motor and sensory nuclei of the thalamus, and in layers III and/or IV of cerebral cortex; in the substantia nigra pars compacts and ventral tegmental area; in the molecular layer of the dentate gyrus and the presubiculum; and in the superficial layers of the superior colliculus. Labelling is conspicuously sparse in the hippocampus and hypothalamus.