WO2022187953A1

WO2022187953A1 - Non-invasive reactivity testing for determining the presence of pathological vascular spasm

Info

Publication number: WO2022187953A1
Application number: PCT/CA2022/050340
Authority: WO
Inventors: Etienne Marc JOLICOEUR; Matthieu PELLETIER-GALARNEAU
Original assignee: Jolicoeur Etienne Marc; Pelletier Galarneau Matthieu
Priority date: 2021-03-10
Filing date: 2022-03-09
Publication date: 2022-09-15

Abstract

The present disclosure concerns imaging agents and triggers for assessing, in a non-invasive manner, a response of a myocardium of a subject to a vascular spasm. The imaging agents and triggers are used to obtain dynamic myocardial perfusion imaging and blood flow quantification of a subject experiencing a vascular spasm. By determining the perfusion and the blood flow of the myocardium of the subject experiencing the vascular spasm, it is possible to determine the presence of a pathological response in the subject.

Description

NON-INVASIVE REACTIVITY TESTING FOR DETERMINING THE PRESENCE OF PATHOLOGICAL VASCULAR SPASM

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority on US provisional application 63/158,950 filed March 10, 2011, the entire content of which is being hereby incorporated by reference.

TECHNOLOGICAL FIELD

[0002] The present disclosure concerns combinations of an imaging agent and a trigger for causing a vascular spasm to determine, in a non-invasive manner, the presence of a pathological response to the vascular spasm. These combinations are used to obtain dynamic myocardial perfusion imaging and blood flow quantification.

BACKGROUND

[0003] A large contingent of patients with atypical chest pain and so-called "normal coronary arteries" are in reality suffering from vasospastic angina (variant angina), a disease caused by abnormal coronary vasomotion. The gold standard to diagnose vasospastic angina is the coronary reactivity testing, which necessitates the intracoronary (IC) injection of ergonovine or acetylcholine, and is performed selectively at dedicated centers. As a result, several patients with vasospastic angina remain undiagnosed and untreated.

[0004] Non-invasive alternatives have been proposed to diagnose vasospastic angina but are sparingly used in individual centers. Historically, intravenous (IV) ergonovine with simultaneous ST segment ECG recording has been used in patients who had recently undergone coronary arteriography. Ergonovine echocardiography can also be used to diagnose vasospastic angina, and the onset of ergonovine-induced wall motion abnormalities have been associated with an adverse prognosis. However, this test does not allow quantification of myocardial perfusion. Single-photon emission computerized tomography (SPECT) myocardial perfusion imaging with exercise stress or hyperventilation is neither sensitive nor specific for the diagnosis of vasospastic angina. In that context, there is an unmet clinical need for the non-invasive investigation of vasospastic angina.

BRIEF SUMMARY

[0005] The present disclosure concerns the non-invasive assessment of a response of a myocardium to a vascular spasm. The present disclosure relies on the use of a combination of an imaging agent allowing for the dynamic myocardial perfusion imaging and blood flow quantification and a trigger capable of causing a vascular spasm, such as, for example, a coronary arterial spasm.

[0006] According to a first aspect, there is provided an imaging agent for dynamic myocardial perfusion imaging and blood flow quantification. The imaging agent is for use in combination with a trigger capable of inducing a vascular spasm. In an embodiment, the imaging agent is a radionuclide or a compound comprising the radionuclide. In another embodiment, the radionuclide is provided in a radionuclide generator. In yet another embodiment, the radionuclide is obtained with a cyclotron. In further embodiments, the imaging agent is suitable for intravenous or intra-arterial administration. In yet another embodiment, the dynamic myocardial perfusion imaging and blood flow quantification is positron emission tomography (PET). In yet additional embodiments, the imaging agent is or comprises ⁸²Rb, ⁱ⁸p, I⁵Q and/or ¹³N. In some embodiments, the radionuclide is ⁸²Rb or an imaging acceptable salt thereof. In additional embodiments, the parent substance capable of generating the radionuclide is ⁸²Sr. In still further embodiments, the trigger is capable of inducing a coronary arterial spasm. In yet another embodiment, the trigger is a substance suitable for administration to a subject. In some additional embodiments, the trigger is suitable for intravenous administration, intracoronary or oral administration or inhalation. In yet some further embodiments, the substance is an adrenergic receptor agonist. In some embodiments, the adrenergic receptor agonist is adrenaline, noradrenaline, amphetamine, methylphenidate, cocaine, vasopressin, derivatives thereof or combinations thereof. In yet another embodiment, the substance is capable of limiting endothelial-dependent vasodilatation. In some further embodiments, the substance is ergonovine, acetylcholine, metacholine, ergotamine, neuropeptide Y, derivatives thereof or combinations thereof. In some further embodiments, the substance is ergonovine. In yet some additional embodiments, the trigger comprises a physical and/or a mental stress.

[0007] According to a second aspect, there is provided a trigger capable of inducing a vascular spasm. The trigger is for use in combination with an imaging agent for dynamic myocardial perfusion imaging and blood flow quantification. In an embodiment, the imaging agent is a radionuclide or a compound comprising the radionuclide. In another embodiment, the radionuclide is provided in a radionuclide generator. In yet another embodiment, the radionuclide is obtained with a cyclotron. In further embodiments, the imaging agent is suitable for intravenous or intra-arterial administration. In yet another embodiment, the dynamic myocardial perfusion imaging and blood flow quantification is positron emission tomography (PET). In yet additional embodiments, the imaging agent is or comprises ⁸²Rb, ¹⁸F, ¹⁵0 and/or ¹³N. In some embodiments, the radionuclide is ⁸²Rb or an imaging acceptable salt thereof. In additional embodiments, the parent substance capable of generating the radionuclide is ⁸²Sr. In still further embodiments, the trigger is capable of inducing a coronary arterial spasm. In yet another embodiment, the trigger is a substance suitable for administration to a subject. In some additional embodiments, the trigger is suitable for intravenous administration, intracoronary or oral administration or inhalation. In yet some further embodiments, the substance is an adrenergic receptor agonist. In some embodiments, the adrenergic receptor agonist is adrenaline, noradrenaline, amphetamine, methylphenidate, cocaine, vasopressin, derivatives thereof or combinations thereof. In yet another embodiment, the substance is capable of limiting endothelial-dependent vasodilatation. In some further embodiments, the substance is ergonovine, acetylcholine, metacholine, ergotamine, neuropeptide Y, derivatives thereof or combinations thereof. In some further embodiments, the substance is ergonovine. In yet some additional embodiments, the trigger comprises a physical and/or a mental stress.

[0008] According to a third aspect, there is provided a combination of an imaging agent for dynamic myocardial perfusion imaging and blood flow quantification and a trigger capable of inducing vascular spasm. In an embodiment, the imaging agent is a radionuclide or a compound comprising the radionuclide. In another embodiment, the radionuclide is provided in a radionuclide generator. In yet another embodiment, the radionuclide is obtained with a cyclotron. In further embodiments, the imaging agent is suitable for intravenous or intra arterial administration. In yet another embodiment, the dynamic myocardial perfusion imaging and blood flow quantification is positron emission tomography (PET). In yet additional embodiments, the imaging agent is or comprises ⁸²Rb, ¹⁸F, ¹⁵0 and/or ¹³N. In some embodiments, the radionuclide is ⁸²Rb or an imaging acceptable salt thereof. In additional embodiments, the parent substance capable of generating the radionuclide is ⁸²Sr. In still further embodiments, the trigger is capable of inducing a coronary arterial spasm. In yet another embodiment, the trigger is a substance suitable for administration to a subject. In some additional embodiments, the trigger is suitable for intravenous administration, intracoronary or oral administration or inhalation. In yet some further embodiments, the substance is an adrenergic receptor agonist. In some embodiments, the adrenergic receptor agonist is adrenaline, noradrenaline, amphetamine, methylphenidate, cocaine, vasopressin, derivatives thereof or combinations thereof. In yet another embodiment, the substance is capable of limiting endothelial-dependent vasodilatation. In some further embodiments, the substance is ergonovine, acetylcholine, metacholine, ergotamine, neuropeptide Y, derivatives thereof or combinations thereof. In some further embodiments, the substance is ergonovine. In yet some additional embodiments, the trigger comprises a physical and/or a mental stress.

[0009] According to a fourth aspect, the present disclosure concerns a method of assessing a response of a myocardium of a subject to a vascular spasm. The method comprises performing dynamic myocardial perfusion imaging and blood flow quantification when the subject experiences a vascular spasm and determining the response of the subject (which may, in some embodiments, be considered to be a pathological response) based on the dynamic myocardial perfusion imaging and blood flow quantification. In some embodiments, the method further comprises acquiring a myocardial perfusion image in the absence of the vascular spasm. In additional embodiments, the method further comprises acquiring a myocardial perfusion image at maximal dilation of the vessels of the myocardium. In yet additional embodiments, the method comprises performing dynamic myocardial perfusion imaging and blood flow quantification with positron emission tomography (PET). In an embodiment, the method comprises determining the pathological response when a partial perfusion and/or a reduction in the blood flow is present. In still another embodiment, the subject had received an imaging agent as described herein. In an embodiment, the method further comprises administering the imaging agent to the subject. In a further embodiment, a trigger as described herein has been administered to the subject. In some additional embodiments, the method further comprises administering the trigger to the subject. In yet another embodiment, the method comprises administering the trigger to the subject before administering the imaging agent. In some embodiments, the subject is at risk of experiencing a vasospastic angina, a microvascular spasm or a macrovascular spasm. In some additional embodiments, the vasospastic angina is a diffuse macrovascular spasm.

[0010] According to a fifth aspect, the present disclosure provides a method of diagnosing and treating a vasospastic angina, a microvascular spasm or a macrovascular spasm in a subject. The method comprises determining the presence of a pathological response to a vascular spasm in the subject as described herein and administering a therapy to the subject when the pathological response to the vascular spasm has been determined to be present. In some additional embodiments, the vasospastic angina is a diffuse macrovascular spasm.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Having thus generally described the nature of the invention, reference will now be made to the accompanying drawings, showing by way of illustration, a preferred embodiment thereof, and in which: [0012] Figure 1 provides the results of dipyridamole ^99mTc-sestamibi perfusion imaging of a 71-year-old male patient. Abbreviations: Dip, dipyridamole; LAO, left oblique anterior; OM, obtuse marginal; RAO, right oblique anterior; To, technetium.

[0013] (Figure 1a) The dipyridamole ^99mTc-sestarnibin myocardial perfusion study showed a large reversible perfusion defect in the inferolateral and lateral walls, corresponding to the circumflex territory.

[0014] (Figure 1b) A critical stenosis of the large second obtuse marginal (OM2) artery persisted despite intracoronary nitroglycerine and was successfully treated with a 3.5 x 15 mm stent (arrowhead, right panel). The right coronary artery is tortuous and presents multiple non-obstructive (<30%) coronary plaques.

[0015] Figure 2 provides the results of a provocative intracoronary testing with ergonovine of a 71-year-old male patient. Intracoronary ergonovine triggered the usual chest pain and significant ST-segment depressions in the perfused territory of both arteries, with a predominant response in the right coronary artery. Of note, a spasm distal to the OM2 stent can be seen (arrowhead). Abbreviations: LAO, left oblique anterior; OM, obtuse marginal; RAO, right oblique anterior.

[0016] Figure 3 provides the results of a ⁸²Rb positron emission tomography perfusion imaging with intravenous ergonovine of a 71-year-old male. Abbreviations: Rb, rubidium.

[0017] (Figure 3a) ⁸²Rb PET-MPI performed immediately after intravenous administration of ergonovine revealed a moderately large perfusion defect in the inferoseptal wall, corresponding to the right coronary artery territory, which was not seen on resting images. This also could not be seen with the ^99mTc-sestarnibi perfusion imaging (see Figure 1).

[0018] (Figure 3b) Flow quantification assessed with ⁸²Rb PET-MPI revealed a significant reduction in myocardial blood flow in the right coronary artery territory, from 0.4 mL/min/g at rest to 0.1 mL/min/g following administration of IV ergonovine. Myocardial blood flow remained essentially unchanged in the other coronary territory.

[0019] Figure 4 provides the results of ⁸²Rb-PET myocardial perfusion imaging (⁸²Rb-PET- MPI) of a 71-year old male patient (with vasospastic angina) with in a control patient without vasospastic angina revealed no induction of perfusion defect. [0020] (Figure 4a) ⁸²Rb-PET-MPI was performed immediately after administration of intravenous ergonovine in a control patient (without vasospastic angina). No perfusion defect were observed.

[0021] (Figure 4b) ⁸²Rb-PET-MPI was performed immediately after administration of intravenous ergonovine in a 71-year old male patient with confirmed vasospastic angina (as shown on Figure 3b). Non-invasive reactivity testing revealed a moderately large perfusion defect in the inferoseptal wall of this patient, corresponding to the right coronary artery territory, which was not observed on resting images.

DETAILED DESCRIPTION

[0022] The present disclosure concerns the use of dynamic imaging of myocardial perfusion and the quantification of blood flow in a subject. The present disclosure relies on the use of imaging during the distribution phase of an imaging agent to quantify the perfusion and blood flow of the myocardium of a subject experiencing a vascular spasm. The quantitative and dynamic imaging can be used to determine if the subject experiences a pathological spasm (such as, for example, an abnormal coronary vasomotion) and to help in the diagnosis of a vasospastic angina (including, but not limited to diffuse vasospastic angina), a microvascular spasm and/or a macrovascular spasm. The subject can be a mammalian subject, such as for example a human. The subject can be a female or a male subject. The subject can be an adult subject. The subject can be a pediatric subject.

[0023] In the context of the present disclosure, the imaging is performed at least during the distribution phase of the imaging agent used. Optionally, the imaging can also be performed during the equilibrium phase of the imaging agent used. As used in the context of the present disclosure, the “distribution phase” of the imaging agent refers to a period of time in which the imaging agent distributes in various tissues (e.g. , the myocardium) and biological fluids (e.g. , blood) of the subject. During the distribution phase of the imaging agent, the presence, the location and the intensity of signal(s) associated with the imaging agent substantially changes with time. In some embodiments, during the distribution phase of the imaging agent, the time-activity curve of the imaging agent substantially increases and substantially decreases. After the distribution phase of the imaging agent, the presence, the location and the intensity of signal(s) associated with the imaging agent do not substantially change and eventually reach a plateau. This plateau is known in the art as the “equilibrium phase” of the imaging agent. In some embodiments, during the equilibrium phase of the imaging agent, the time-activity curve of the imaging agent does not substantially increases nor substantially decreases, and instead slowly decreases or slowly increases with time. The “equilibrium phase” of an imaging agent is a period in which the imaging agent has been distributed in the various tissues (e.g. , the myocardium) and biological fluids (e.g. blood) of the subject.

[0024] The quantitative and dynamic imaging technique allows the quantification of the perfusion and the blood flow of the myocardium. In some embodiments, the quantitative and dynamic imaging techniques allows the quantification of the myocardial and/or the coronary flow reserve of the myocardium.

[0025] The quantitative and dynamic imaging technique that can be used to quantify the perfusion and blood flow of the myocardium relies on the use of an imaging agent. The imaging agent is intended to be administered to a subject in which the quantitative and dynamic imaging is intended to be performed. The imaging agent is capable of being used in a quantitative and dynamic imaging technique. The imaging agent is the substance that is intended to be administered to the subject prior to imaging so as to allow the quantitative and dynamic imaging. The imaging agent is able to emit a signal (in some embodiments a radioactive signal) that can be detected with an image acquisition system to determine the distribution of the imaging agent in the myocardium (including in the blood vessels of the myocardium), so as to allow the quantification of the perfusion and the blood flow of the myocardium of the subject.

[0026] In some embodiments, the imaging agent can comprise a radionuclide (also known as a radioactive nuclide, a radioisotope or a radioactive isotope). For example, the imaging agent can be the radionuclide itself. In another example, the radionuclide can be included in a compound (usually referred to as a radiotracer) along with other non-radioactive elements. In such embodiment, the compound comprising the radionuclide will be considered to be the imaging agent.

[0027] The radionuclide that is present in the imaging agent can be generated using a cyclotron. Alternatively or in combination, the radionuclide can be provided as a parent substance capable of generating the imaging agent as a daughter substance. This embodiment is particularly useful for radionuclides having short half-lives, such as, for example ⁸²Rb. In embodiments in which the imaging agent is generated from a parent substance, the parent substance can be provided in a radionuclide generator. In such embodiment, the daughter substance capable of being obtained from the parent substance will be considered to be the imaging agent.

[0028] The imaging agent is intended to be used to perform quantitative and dynamic imaging of the myocardium to obtain a quantitative measurements of the perfusion of the myocardium and the blood flow of the myocardium. In some embodiments, the imaging agent is suitable for intravenous or intra-arterial (including, but not limited to, intra-coronary) administration. For example, the imaging agent can be provided in an imaging composition for intravenous or intra-arterial (including, but not limited to intra-coronary) administration. In some embodiments, the imaging agent is suitable for administered during an interventional procedure. For example, the imaging agent can be provided in an imaging composition for administration during an intervention. In yet another specific example, the imaging agent can be provided in an imaging composition is for the intravenous administration of the imaging agent. As used in the context of the present disclosure, an “imaging composition” refers to a composition comprising the imaging agent and an imaging acceptable excipient. The term “imaging acceptable excipient” refers to a physiologically acceptable solvent, suspending agent or any other inert vehicle for delivering the imaging agent and that will not substantially interfere with the imaging properties of the imaging agent. In some embodiments, the imaging composition can include further components such as, for example, an additive, a preservative and/or a buffer. In further embodiments, the imaging composition does not include further components (besides the imaging agent and the excipient) and as such is considered to be “additive free”.

[0029] The imaging agent can be provided in a liquid (e.g. , a solution) for administration to the subject. In the context of the present disclosure, the imaging agent is provided to the subject in an amount sufficient to allow the quantitative and dynamic imaging of the myocardium of the subject. In some embodiments, the imaging agent can be provided in an imaging acceptable salt form in the imaging composition. The expression "imaging acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the imaging properties of the imaging agent and are formed from suitable organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base- addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as e.g., tetramethylammonium hydroxide. The chemical modification of an imaging agent into a salt is a well known technique which can be used to improve, when possible, the properties of the imaging agent such as, for example, its physical or chemical stability. [0030] In the methods described herein, the imaging agent is provided in an amount sufficient (e.g. , an imaging effective amount) to allow the quantitative and dynamic imaging technique. The imaging agent can be provided in a single dose or in multiple doses to achieve the imaging effective amount. In an embodiment, the imaging agent can be provided in a single dose.

[0031] The quantitative and dynamic imaging technique that can be used to quantify the perfusion and blood flow of the myocardium can be, without limitation positron emission tomography (PET), magnetic resonance imaging (MRI), computerized tomography scanner (CT-scan) or combinations thereof. In a specific embodiment, the quantitative and dynamic imaging technique that can be used to quantify the perfusion and blood flow of the myocardium is positron emission tomography (PET). In some embodiments, the quantitative and dynamic imaging technique is not computerized tomography (CT), single-photon emission computerized tomography (SPECT), an angiography and/or a echography, since these techniques cannot be performed to obtain a quantitative assessment of myocardial perfusion and blood flow. When PET is used as the quantitative and dynamic imaging technique, an imaging agent capable of emitting positrons and distributing in the myocardium proportionally to myocardial perfusion can be used. Imaging agents that can be used with PET in the methods of the present disclosure include, but are not limited to, imaging agents being or comprising ⁸²Rb, ¹⁸F, ¹⁵0, ¹³N as well as mixtures thereof. Imaging agents that can be used with MRI in the methods of the present disclosure include, but are not limited to, gadolinium-based contrast agents. Imaging agents that can be used with the CT scan include but are not limited to iodine-based contrast medium.

[0032] In one specific embodiment, the imaging agent is or comprises ⁸²Rb. In embodiments in which the imaging agent is ⁸²Rb, it can be provided in an imaging acceptable salt form, such as, for example, a chloride salt form. Furthermore, the imaging agent ⁸²Rb can be provided from a radionuclide generator comprising ⁸²Sr as the parent radionuclide. When used in human subjects for myocardial imaging, ⁸²Rb can be administered at a dose of 740- 1100 MBq/injection. Known systems capable of providing ⁸²Rb as the imaging agent include, without limitation, CardioGen-82® and Ruby-Fill® (both provided in a radionuclide generator).

[0033] In another specific embodiment, the imaging agent is or comprises ¹⁸F. In an embodiment in which the imaging agent is a compound comprising ¹⁸F, it can be provided as fluripiridaz and have the following formula (I):

[0034] The radionuclide ¹⁸F can be provided from a cyclotron. When used in human subjects for myocardial imaging, the imaging agent comprising ¹⁸F can be administered at a dose of 185-370MBq/injection.

[0035] In still a further embodiment, the imaging agent is or comprises ¹⁵0. In embodiments in which the imaging agent is a compound comprising ¹⁵0, it can be provided as ¹⁵0-H₂0. Furthermore, the radionuclide ¹⁵0 can be generated from a cyclotron. When used in human subjects for myocardial imaging, ¹⁵0 can be administered at a dose of 740 MBq/injection.

[0036] In still a further embodiment, the imaging agent is or comprises ¹³N. In embodiments in which the imaging agent is a compound comprising ¹³N, it can be provided as ¹³N-NH_3. Furthermore, the radionuclide comprising ¹³N can be generated from a cyclotron. When used in human subjects for myocardial imaging, ¹³N can be administered at a dose of 370-1100 MBq/injection.

[0037] In the context of the present disclosure, the imaging agent is intended to be administered to a subject experiencing a vascular spasm, such as, for example, an arterial (e.g. , coronary) spasm. In order to achieve this, the imaging agent is used in combination with a trigger known to cause a vascular spam. It is recognized in the art that triggers capable of causing a vascular spasm fall into one of the two following categories of mechanism of action: activation of adrenergic receptors and endothelial-dependent vasodilatation. The trigger can be a substance which is intended to be administered to the subject to cause a vascular spasm. The substance can be administered in a single dose or in multiple doses to cause the vascular spasm. The substance can be provided in a pharmaceutical composition comprising a pharmaceutically acceptable excipient. The substance can be provided in an amount sufficient (in one or more doses) to cause a vascular spasm in the subject. The substance can be provided in increasing amounts to the subject until a vascular spasm is observed in the subject. The trigger can be a physical or a mental stress which is intended to be imposed to the subject to cause a vascular spasm. The physical stress can be imposed once or a plurality of time to cause the vascular spasm. In some embodiments, the trigger can be a combination of a substance and a physical stress. The trigger is administered/imposed on the subject until a vascular spasm is observed or detected in the subject. In some embodiments, the trigger is administered/imposed to cause a vascular spasm in the subject. The presence of a chest pain is indicative of a vascular spasm and can be used to determine that a vascular spasm is present in the subject. Alternatively or in combination, a change in the subject’s electrocardiogram (ECG) can be indicative of the presence of a vascular spasm in the subject. Transient ischemic ECG changes during spontaneous episode including any of the following in at least two contiguous leads: (a) ST segment elevation > 0.1 mV, (b) ST segment depression > 0.1 mV, (c) new negative U waves are indicative of the presence of a vascular spasm in the subject. The presence of transient or total or subtotal coronary artery occlusion (>90% constriction) with angina as determined by ischemic ECG changes and/or coronary arteriography is indicative of the presence of the vascular spasm in the subject. Once the vascular spasm is observed/detected in the subject, the subject can receive the imaging agent and be submitted to the quantitative and dynamic imaging.

[0038] When the trigger used to cause a vascular spasm is a substance to be administered to the subject, such substance is suitable for administration to the subject. In some embodiments, the trigger used to cause the vascular spasm is suitable for intravenous, intra arterial (including, but not limited to, intra-coronary), oral administration or inhalation. In some additional embodiments, the trigger does not cause a substantial vasodilatation.

[0039] One of the trigger that can be administered/imposed on the subject can be a substance known to cause the activation of one or more adrenergic receptor (e.g. , be an adrenergic agonist) in the subject. In humans, the adrenergic receptors present on nerve cells and are a class of G-coupled receptors classified into two main groups (a (including cu (a-i_A, a-i_B, a-i_D subtypes) and a₂ types (<¾_A, a_2B and a_2C subtypes)) and b (including b-i, b₂ and b₃) types). In some embodiments, the adrenergic receptor agonist can be specific for a single adrenergic receptor group, a single adrenergic receptor type or a single adrenergic receptor subtype. In some additional embodiments, the adrenergic receptor agonist can be specific for more than one single adrenergic receptor group, more than one single adrenergic receptor type or more than one single adrenergic receptor subtype. In some further embodiments, the adrenergic receptor agonist can be exert its effects on all adrenergic receptor groups, types and subtypes. In some embodiments, the adrenergic receptor agonist can be a ligand of one or more adrenergic receptor. Adrenergic receptor agonists include, without limitation, adrenaline, noradrenaline, amphetamine, methylphenidate, cocaine, vasopressin, derivatives thereof, as well as combinations thereof.

[0040] One of the trigger that can be administered on the subject can be a substance known to limit endothelial-dependent vasodilatation. In some embodiments, the trigger can be the administration of a substance capable of acting on smooth muscle mainly via activation of serotonergic (5-HT ₂) receptors to produce vasoconstriction, such as, for example, ergonovine (which is suitable, in some embodiments, to intravenous or intracoronary administration), ergotamine or a derivative thereof. In further embodiments, the trigger can be the administration of a substance capable of acting on the endothelium and smooth muscle via muscarinic receptors and causing, in the setting of endothelial dysfunction, a reduction in the production of nitric oxide by endothelial cells, resulting in blood vessel contraction rather than vasodilation. In such embodiments, the trigger can be acetylcholine (which is suitable, in some embodiments, to intra-arterial (intra-cardiac) administration), metacholine (which is suitable, in some embodiments, to administration by inhalation) or a derivative thereof. Additional substances capable of causing a vasospasm include, but are not limited to, ergotamine, neuropeptide Y, dopamine, derivatives thereof and combinations thereof.

[0041] One of the trigger that can be imposed on the subject can be a physical or a mental stress known to limit endothelial-dependent vasodilatation. Such trigger include, without limitation, a cold pressor test (e.g. , partial or total immersion of a body part in ice-cold water), hyperventilation and/or mental stress provocation (e.g., causing an alpha adrenergic mediated increase in coronary vascular resistance and the induction of hemodynamic changes and ultimately cause a release of noradrenaline).

[0042] After the trigger has been administered/imposed on the subject and the latter will eventually experience a vascular spasm and can be submitted to dynamic myocardial perfusion imaging and blood flow quantification. The subject experiencing a vascular spasm is intended to receive the imaging agent and can be submitted to imaging. As such, the method of the present disclosure comprises performing dynamic myocardial perfusion imaging and blood flow quantification when the subject experiences a vascular spasm (caused by the trigger). As indicated above, the myocardial perfusion and blood flow imaging is performed at least during the distribution phase of the imaging agent. Concurrently or after the imaging has been performed, it is determined the type of response of the myocardium of the subject that occurred in response to the vascular spasm (which may, in some embodiments, be a pathological response). This determination is based on the dynamic myocardial perfusion imaging and blood flow quantification performed when the subject experiences the vascular spasm. The determination can include determining if a partial perfusion defect and/or a reduction of the blood flow of the subject’s myocardium is present when the subject experiences the vascular spasm.

[0043] The presence of a pathological response to a vascular spasm determined according to the methods of the present disclosure is indicative of that the subject is at risk of having or experiencing a vasospastic angina, a microvascular spasm or a macrovascular spasm. The macrovascular spasm can be focal or diffuse. As such, the presence of a pathological response to the vascular spasm determined according to the methods of the present disclosure and can be used in the diagnosis of these conditions.

[0044] In some embodiments, it is contemplated to also acquire one or more myocardial perfusion images (which can include, for example, information about the perfusion of the myocardium and/or the blood flow in the myocardium) of the subject’s myocardium prior to the onset of the vascular spasm (e.g. , prior to the administration/imposition of the trigger) and/or during the equilibrium phase of the imaging agent. These further myocardial perfusion images (obtained during the equilibrium phase of the imaging agent) can be used to confirm the presence of a pathological response to a vascular spasm. The myocardial perfusion images obtained during the equilibrium phase of the imaging agent could be used, for example, to assess ventricular function, regional wall motion and/or ventricular volume. In some embodiments, theses further myocardial perfusion images can be acquired under static conditions. In some embodiments, these further myocardial perfusion images (obtained during the equilibrium phase of the imaging agent) may not be useful for the determination of a risk of experiencing or having a diffuse macrovascular spasm or a microvascular spasm in the subjects as these conditions, under the equilibrium phase of the imaging agent, may not exhibit a detectable pathological response.

[0045] In some embodiments, it is contemplated to acquire one or more myocardial perfusion images (which can include, for example, information about the perfusion of the myocardium and/or the blood flow in the myocardium) of the subject’s myocardium at maximal dilation of the vessels of the myocardium.

[0046] In some embodiments, it is contemplated to acquire one or more additional image(s) to evaluate the myocardial wall motion of the myocardium.

[0047] In some additional embodiments, it is contemplated to acquire one or more additional image(s) to quantity the coronary and/or the myocardial flow reserve. [0048] The methods described herein can rely on the use of any imaging technique capable of providing dynamic myocardial perfusion imaging and blood flow quantification. In an embodiment, the methods described herein can rely on the use of positron emission tomography (PET) to perform dynamic myocardial perfusion imaging and blood flow quantification when the subject experiences a vascular spasm.

[0049] The subjects whose response to a vascular spasm are assessed experience, during the performance of imaging, a vascular spasm. In some embodiments, the subject has been administered or imposed with a trigger (e.g., a substance or a physical stress) as described herein prior to performing dynamic myocardial perfusion imaging and blood flow quantification. As such, in some further embodiments, the method can include administering/imposing the trigger as described herein to the subject prior to performing imaging.

[0050] The subjects whose response to a vascular spasm are assessed have, in some embodiments, received an imaging agent which is in its distribution phase during the performance of the imaging. In some embodiments, the subject has been administered with an imaging agent or an imaging composition prior to performing dynamic myocardial perfusion imaging and blood flow quantification. As such, in some further embodiments, the method can include administering the imaging agent or the imaging composition as described herein to the subject prior to performing imaging. It is understood that the imaging agent can be administered after the trigger and, in some embodiments, only in subjects experiencing symptoms or signs suggestive of vascular spasms.

[0051] In an embodiment, the methods of the present disclosure should be used with caution in subjects with unstable coronary syndromes or in the absence of knowledge of the coronary anatomy of the subjects. As such, the method can be performed in subjects which do not experience an unstable coronary syndrome and/or have no obstructive coronary artery disease. In some embodiments, the methods of the present disclosure can include determining the presence/absence of an unstable coronary syndrome in the subject prior to the administration/imposition of the trigger. In some further embodiments, the methods of the present disclosure can include determining the presence/absence of obstructive coronary artery disease prior to the administration/imposition of the trigger.

[0052] The methods of the present disclosure can be used, for example, in the diagnosis of vasospastic angina and/or to determine the presence or risk of developing a macrovascular spasm or a microvascular spam in the subject. The methods of the present disclosure do not allow determining if an endothelial dysfunction has occurred in the subjects, and instead seek at determining the risk of subject (e.g., the predisposition of the subject) to experience of vascular spasm (such as a macro- or a microvascular spasm) which can be focal or diffuse. When it is determined that the subject exhibits a pathological response to the vascular spasm, the subject is considered at high risk (e.g., is predisposed) to experience a macro- and/or a microvascular spasm, when compared to one or more control subject known not to experience a macro- and/or microvascular spasm. When it is determined that the subjects does not exhibit a pathological response to the vascular spasm, the subject is considered at low risk (e.g., is not predisposed) to experience a macro- and/or a microvascular spasm. In such embodiments, additional diagnostic information can be obtained from an electrocardiogram, a coronary arteriography and/or other imaging techniques to confirm the determination made.

[0053] Since the presence of a pathological response to a vascular spasm in the subject is indicative that the subject is at risk of experiencing or has vasospastic angina, a macrovascular spasm or a microvascular spasm, the method can be used to prevent or treat such conditions and can further include, in some embodiments, administering a therapy to the subject when the pathological response to the vascular spasm has been determined to be present. The therapy can be a known therapy for the prevention or the treatment of vasospatic angina. The therapy can including administering one or more therapeutic agent, intervention, and/or recommending avoiding certain therapeutic agents or noxious stimuli. In some embodiments, the therapy can include administering one or more dose of a vasodilator such as, for example, a short and long-acting nitrate, a calcium channel blocker (which can be a non-dihydropyridine and/or a dihydropyridine calcium channel blocker such as, for example, verapamil or diltiazem), a direct NO giver and potassium channel opener (such as, for example, nicorandil), a rho kinase inhibitor (such as, for example, fasudil), an inhibitor of phosphodiesterase III (such as, for example, cilostazol) and/or a peroxisome proliferator- activated receptor gamma (PPAR-g) activator (such as, for example, pioglitazone) to the subjects. Additional vasodilators include, but are not limited to estradiol (especially in postmenopausal women), vitamin C, glutathione, a combination of guanethidine and clonidine, a corticosteroid and/or magnesium sulfate.

[0054] In some embodiments, the therapy can include avoiding administering or discontinuing administering one or more dose of a vasospastic drug, such as, for example, a b-blocker.

[0055] In some embodiments, the therapy can include the avoidance of one or more noxious stimulus, such as, for example, smoking, alcohol consumption, ergot derivatives, cocaine and/or other sympathomimetics. [0056] In some further embodiments, the therapy can include performing a left stellate ganglion blockade and/or surgical thoracic sympathectomy.

[0057] The methods of the present disclosure can be used in pre-clinical or clinical trials. In some embodiments, the methods of the present disclosure can be used to include or exclude a subject in a pre-clinical or a clinical trial. In such embodiments, the presence of a pathological response to the vascular spasm can be used as an inclusion or an exclusion criteria. For example, the methods of the present disclosure can be used to include (e.g. , as an inclusion criteria) subjects at risk or experiencing a pathological spasm caused by the trigger. In another example, the methods of the present disclosure can be used to exclude (e.g., as an exclusion criteria) subjects at risk or experiencing a pathological spasm caused by the trigger. In other embodiments, the methods of the present disclosure can be used to classify a subject during a pre-clinical or clinical trial. For example, the methods of the present disclosure can be used to include/exclude a subject at risk or experiencing a pathological spasm caused by trigger in a class of subjects in the pre-clinical or clinical trial.

[0058] The methods of the present disclosure can be used, for example, as a companion diagnostic for therapeutics for vasospastic angina and/or for limiting the onset, duration of frequency of a macrovascular spasm or a microvascular spam in the subject. In an embodiment, the methods of the present disclosure can be used to determine if a subject would benefit from receiving a therapy for the prevention or the treatment of vasospastic angina, a macrovascular spasm or a microvascular spam in the subject. In such embodiment, the method can be performed prior to receiving the therapy and the results of the method can be used to guide the selection of the therapy. In such embodiment, the method can include indicating that the therapy would be useful or not in the subject.

[0059] The methods of the present disclosure can be used, for example, as a monitoring tool for therapeutics for vasospastic angina and/or for limiting the onset, duration of frequency of a macrovascular spasm or a microvascular spam in the subject. In an embodiment, the methods of the present disclosure can be used to determine if a subject would benefit from continuing receiving a therapy for the prevention or the treatment of vasospastic angina, a macrovascular spasm or a microvascular spam in the subject. In such embodiment, the method can be performed after the subject received at least one dose of the therapy and the results of the method can be used to guide if the therapy should be continued or not. As such, the method can include indicating that the therapy should be continued or not in the subject. EXAMPLE

[0060] A 71 -year-old male with hypertension and history of smoking who presented with a new onset atypical chest pain was referred for an exercise treadmill stress test which revealed ST-segment depressions in the inferior and lateral leads at 6 METS. Subsequently, a dipyridamole ^99mTc-sestarnibi myocardial perfusion study showed a large reversible perfusion defect in the inferolateral and lateral walls, corresponding to the circumflex territory (Figure 1a).

[0061] The patient was referred for a coronary angiography where a critical (>90%) stenosis of a large second obtuse marginal (OM2) artery was seen. This lesion persisted despite intracoronary nitroglycerine and was successfully treated with a 3.5 x 15 mm drug eluting stent (Figure 1b; arrowhead, right panel). The remaining of the coronary vasculature was remarkable for its tortuosity and for the presence of multiple non-obstructive (<30%) coronary plaques.

[0062] Two days later, before hospital discharge, the patient experienced recurrent atypical chest pain with a normal ECG and no elevation in high sensitivity troponins. An exercise treadmill stress test was repeated and led to ST-segment elevations in the inferior leads at 3 METS and triggered hypotension. A second coronary angiography performed the same day showed a patent OM2 stent and no new coronary lesion. Instantaneous wave-free ratio (IFR) measured in all three arteries yielded no meaningful ischemia (all iFRs above 0.95). The patient was discharge with a long-acting nitrate combined with a dihydropyridine calcium channel blocker (CCB).

[0063] In spite of dual therapy, the atypical chest pain persisted for two weeks and the patient was referred for vascular reactivity testing (Figure 2). The suspicion of vasospastic angina was confirmed with the intracoronary injection of ergonovine in the right (40 meg) and left (60 pg) coronary arteries. Ergonovine triggered the usual chest pain and significant ST- segment depressions in the perfused territory of both arteries, with a predominant response in the right coronary artery (RCA). Of note, a spasm distal to the OM2 stent can be seen (arrowhead). The coronary spasms and chest pain were immediately reversible with intracoronary nitroglycerine. The patient was discharged with the addition of a non- dihydropyridine CCB.

[0064] Atypical angina persisted despite two weeks of maximal tolerated doses of guideline- directed triple-therapy. At this stage, it appeared inappropriate to repeat a fourth invasive coronary angiography to reassess vasoreactivity. Instead, a Rubidium-82 positron emission tomography myocardial perfusion imaging (⁸²Rb PET-MPI) with incremental doses of IV ergonovine was proposed to assess vasospastic activity. After IV administration of 150 mg of ergonovine, the patient experienced his usual chest pain and displayed 2 mm ST-segment elevations in the inferior leads with reciprocal changes in the lateral leads. At that moment, ⁸²Rb was injected over 30 seconds and PET acquisition was initiated. ⁸²Rb PET-MPI performed following IV ergonovine administration revealed a moderately large perfusion defect in the inferoseptal wall, corresponding to the RCA territory, which was not seen on resting images (Figures 3a and 4b). Flow quantification assessed with ⁸²Rb PET-MPI revealed a significant reduction in myocardial blood flow in the RCA territory following administration of IV ergonovine (Figures 3b and 4b). Such reduction in myocardial blood flow which was absent in a control patient without vasospastic angina (Figure 4a). Myocardial blood flow remained essentially unchanged in the other coronary territory. ⁸²Rb PET-MPI with flow quantification confirmed the presence of a refractory vasospastic angina. Following the test, the patient was discharge with an additional Nicorandil 20 mg (direct NO giver) twice daily and has remained asymptomatic since.

[0065] Vasospastic angina is difficult to diagnose as it typically escapes the traditional investigative pathway of stress testing, non-invasive imaging, and coronary angiography. Often, the coronary arteries are deemed normal, and vasomotion is not properly assessed.

[0066] In this case, ⁸²Rb PET-MPI with IV ergonovine enabled an accurate localization of the vasospasm and a precise quantification of tissue perfusion in all three coronary artery territories and confirmation of persistent abnormal vasoreactivity led to a change in medical management. The ⁸²Rb PET-MPI lead to an additional ~3 mSv in effective radiation dose, which compares favorably to what would have been expected with an additional coronary angiography. This case highlights the feasibility and the potential of ⁸²Rb PET-MPI with IV ergonovine for the investigation of vasospastic angina. Ergonovine ⁸²Rb PET-MPI bears to potential to define new phenotypes (regional vs. diffuse spams) or syndromes (epicardial vs. microvascular spasms), and to monitor response to therapy.

[0067] Importantly, IV ergonovine provocation testing should not be performed in patients with unstable coronary syndromes, and until additional experience is available, should not be performed without knowledge of the coronary anatomy (no obstructive coronary artery disease).

[0068] While the invention has been described in connection with specific embodiments thereof, it will be understood that the scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

Claims

WHAT IS CLAIMED IS:

1. An imaging agent for dynamic myocardial perfusion imaging and blood flow quantification for use in combination with a trigger capable of inducing a vascular spasm.

2. A trigger capable of inducing a vascular spasm for use in combination with an imaging agent for dynamic myocardial perfusion imaging and blood flow quantification.

3. A combination of an imaging agent for dynamic myocardial perfusion imaging and blood flow quantification and a trigger capable of inducing vascular spasm.

4. The imaging agent of claim 1, the trigger of claim 2 or the combination of claim 3, wherein the imaging agent is a radionuclide or a compound comprising the radionuclide.

5. The imaging agent, the trigger or the combination of claim 4, wherein the radionuclide is provided in a radionuclide generator.

6. The imaging agent, the trigger or the combination of claim 4, wherein the radionuclide is obtained with a cyclotron.

7. The imaging agent, the trigger or the combination of any one of claims 1 to 6, wherein the imaging agent is suitable for intravenous or intra-arterial administration.

8. The imaging agent, the trigger or the combination of any one of claims 1 to 7, wherein dynamic myocardial perfusion imaging and blood flow quantification is positron emission tomography (PET).

9. The imaging agent, the trigger or the combination of claim 8, wherein the imaging agent is or comprises ⁸²Rb, ¹⁸F, ¹⁵0 and/or ¹³N.

10. The imaging agent, the trigger or the combination of claim 9, wherein the radionuclide is ⁸²Rb or an imaging acceptable salt thereof.

11. The imaging agent, the trigger or the combination of claim 9 or 10, wherein the parent substance capable of generating the radionuclide is ⁸²Sr.

12. The imaging agent, the trigger or the combination of any one of claims 1 to 11, wherein the trigger is capable of inducing a coronary arterial spasm.

13. The imaging agent, the trigger or the combination of any one of claims 1 to 12, wherein the trigger is a substance suitable for administration to a subject.

14. The imaging agent, the trigger or the combination of claim 12 or 13, wherein the trigger is suitable for intravenous administration, intracoronary or oral administration or inhalation.

15. The imaging agent, the trigger or the combination of any one of claims 12 to 14, wherein the substance is an adrenergic receptor agonist.

16. The imaging agent, the trigger or the combination of claim 15, wherein the adrenergic receptor agonist is adrenaline, noradrenaline, amphetamine, methylphenidate, cocaine, vasopressin, derivatives thereof or combinations thereof.

17. The imaging agent, the trigger or the combination of any one of claims 12 to 14, wherein the substance is capable of limiting endothelial-dependent vasodilatation.

18. The imaging agent, the trigger or the combination of claim 17, wherein the substance is ergonovine, acetylcholine, metacholine, ergotamine, neuropeptide Y, derivatives thereof or combinations thereof.

19. The imaging agent, the trigger or the combination of claim 18, wherein the substance is ergonovine.

20. The imaging agent, the trigger or the combination of any one of claims 1 to 19, wherein the trigger comprises a physical and/or a mental stress.

21. A method of assessing a response of a myocardium of a subject to a vascular spasm, the method comprising:

- performing dynamic myocardial perfusion imaging and blood flow quantification when the subject experiences a vascular spasm; and

- determining the response of the subject based on the dynamic myocardial perfusion imaging and blood flow quantification.

22. The method of claim 21, further comprising acquiring a myocardial perfusion image in the absence of the vascular spasm.

23. The method of claim 21 or 22, further comprising acquiring a myocardial perfusion image at maximal dilation of the vessels of the myocardium.

24. The method of any one of claims 21 to 23, comprising performing dynamic myocardial perfusion imaging and blood flow quantification with positron emission tomography (PET).

25. The method of any one of claims 21 to 24, comprising determining the pathological response when a partial perfusion and/or a reduction in the blood flow is present.

26. The method of any one of claims 21 to 25, wherein the subject had received an imaging agent as defined in any one of claims 1 , 4 to 11.

27. The method of claim 26, further comprising administering the imaging agent to the subject.

28. The method of any one of claims 21 to 27, wherein a trigger as defined in any one of claims 2, 12 to 20 has been administered to the subject.

29. The method of claim 27, further comprising administering the trigger to the subject.

30. The method of claim 28, comprising administering the trigger to the subject before administering the imaging agent.

31. The method of any one of claims 20 to 29, wherein the subject is at risk of experiencing a vasospastic angina, a microvascular spasm or a macrovascular spasm.

32. The method of claim 31, wherein the vasospastic angina is a diffuse macrovascular spasm.

33. A method of diagnosing and treating a vasospastic angina, a microvascular spasm or a macrovascular spasm in a subject, the method comprising determining the presence of a pathological response to a vascular spasm in the subject as defined in any one of claims 21 to 32 and administering a therapy to the subject when the pathological response to the vascular spasm has been determined to be present.

34. The method of claim 33, wherein the vasospastic angina is a diffuse macrovascular spasm.