WO2023067337A1

WO2023067337A1 - Imaging of brain lesions

Info

Publication number: WO2023067337A1
Application number: PCT/GB2022/052666
Authority: WO
Inventors: Eugene Teoh; Matthew Miller; Robin HOLMES
Original assignee: Blue Earth Diagnostics Limited
Priority date: 2021-10-22
Filing date: 2022-10-19
Publication date: 2023-04-27
Also published as: AU2022369448A1

Abstract

The present disclosure relates to methods of administering [¹⁸F]-FACBC. The present disclosure also relates to use of [¹⁸F]-FACBC in methods for imaging, diagnosing, and monitoring of brain lesions.

Description

IMAGING OF BRAIN LESIONS

TECHNICAL FIELD

The present invention relates to methods of administering [¹⁸F]-FACBC. The present invention also relates to use of [¹⁸F]-FACBC in methods for imaging and diagnosing brain lesions.

BACKGROUND

Brain metastases, which may be referred to as secondary brain cancer, occur when cancer cells spread from their original primary tumor site to and/or in the brain. Brain metastases are the most common intracranial tumor in adults, occurring in up to 40% of patients with cancer, with approximately 200,000 patients affected each year in the USA. Following localized treatment of brain metastases (increasingly, stereotactic radiosurgery [SRS] alongside neurosurgical resection), close follow-up with serial magnetic resonance imaging (MRI) of the brain is performed to evaluate for recurrent disease. Conventional MRI is currently recommended as the main imaging test (NCCN, 2019) following localized treatment, as it is widely available and offers high spatial resolution, with presence of recurrent disease suggested by increased contrast enhancement (CE) depicting anatomical/structural information. However, conventional MRI (CE-T1 and fluid attenuated inversion recovery [FLAIR]/T2-weighted sequences) has limited specificity due to the incidence of treatment-related changes, including radiation necrosis. These treatment-related changes have similar appearance to true recurrence of disease on conventional MRI, including CE, origin near the primary tumor site, vasogenic edema, growth over time, and mass effect.

No specific feature or combination of features on conventional MRI has been established to differentiate between disease recurrence and treatment-related changes including radiation necrosis and pseudo-progression. Specificity of conventional MRI to diagnose recurrent tumor after SRS using visual reads has been reported to be as low as 19%, with attempts at validating permutations of neuroradiologist-defined measurements reporting specificities of 32% to 41%. Alongside the estimated 25% incidence rate of radiation necrosis, rates of true local recurrence of disease are similar, ranging from 27% to 31%. Therefore, the true prevalence of recurrent disease post-radiotherapy where conventional MRI indicates the possibility of recurrence, can be estimated to be approximately 50%.

Given this area of great diagnostic unmet need, accurate imaging to differentiate disease recurrence from treatment-related changes is valuable for several reasons:

• Identifying treatment-related changes is important to avoid unneeded treatment (e.g., surgery) and erroneously premature termination of potentially effective treatment.

• Accurate scans can inform the management decision of cessation of non-effective treatments, to minimize morbidity from treatment side effects and reduce the economic burden.

• Timely diagnosis of true recurrence can facilitate prompt stratification of patients to further therapies, which may maximize therapeutic benefit and clinical outcome.

• Given the high morbidity and mortality of patients with brain metastases and, therefore, the need for high quality clinical research, such imaging may be pivotal in determining suitability for clinical trial entry, and accurate characterization of investigational therapeutic efficacy. The Food and Drug Administration (FDA) and National Brain Tumor Society (NBTS) have recognized this particular need for certainty on optimal clinical trial endpoints, leading to recent joint efforts to stimulate much needed research and development in this area (FDA/NBTS, 2019).

• Aiding the physician to risk- stratify continuation of a therapeutic regimen (where treatment- related changes can be confidently diagnosed). This may be of particular value in the context of a treatment with a significant side effect profile.

[¹⁸F]-fluoro-2-deoxy-glucose (FDG) is a PET imaging agent for the detection and localisation of many forms of cancer. However, FDG-PET has been found to have less sensitivity and/or specificity for assessment of some types of cancer, for example, brain tumors. Metastasis involves a complex series of steps in which cancer cells leave the primary tumor site and migrate to other parts of the body via the bloodstream or the lymphatic system. The new occurrences of tumor thus generated are referred to as a metastatic lesion or metastasis. Metastatic lesions are very common in the late stages of cancer and are a major cause of death from solid lesions. There are known difficulties associated with diagnosing and monitoring metastatic cancer, for example, obtaining images at different time points with enough accuracy to enable comparison is challenging.

Thus, there is a need for a method of imaging which allows for reproducible, reliable imaging for detection and monitoring of metastatic cancer in the brain.

Thus, there is a need for a method of reproducible, reliable imaging of metastatic cancer in the brain to permit diagnosis of metastatic cancer in the brain.

Thus, there is a need for a method of reproducible, reliable imaging of metastatic cancer in the brain to permit and/or facilitate distinction between metastatic cancer, particularly recurrent metastatic cancer, in the brain and treatment-related changes in the brain, such as radiation necrosis and pseudo-progression.

SUMMARY

Aspects of the present invention relate to methods of diagnosing brain lesions, e.g., analysing potential lesions to determine whether they are brain lesions, in a subject by administering anti-1- amino-3-¹⁸F-fluorocyclobutane-l-carboxylic acid ([¹⁸F]-FACBC) for improved PET imaging and more reliable diagnosis of cancer and the metastasis or recurrence thereof. For example, the present invention relates to methods of administering [¹⁸F]-FACBC for improved PET imaging and more reliable diagnosis of brain lesions and the metastasis or recurrence thereof. The present invention further relates to methods of diagnosing brain lesions and the metastasis or recurrence thereof, using the PET imaging agent [¹⁸F]-FACBC. Still further, the present invention relates to methods of identifying and diagnosing metastatic brain lesion(s), and the recurrence thereof, using the PET imaging agent [¹⁸F]-FACBC, and permitting distinction between the metastatic brain lesion(s) and treatment-related changes in the brain, such as radiation necrosis and pseudo-progression.

In particular, although not exclusively, the present invention may include making a comparison of the uptake of [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]-FACBC uptake in the venous sinus blood pool of the brain. Typically, this comparison may allow for a more accurate diagnosis of the potential lesion than using MRI and/or CT alone, e.g. diagnosing brain lesions and/or the metastasis or recurrence thereof.

In particular, although not exclusively, the present invention may include making a comparison of a standardized uptake value (SUV) of the [¹⁸F]-FACBC uptake in a potential lesion against a reference threshold standardized uptake value (SUV)threshoid. Typically, this comparison may allow for a more accurate diagnosis of the lesion than using MRI and/or CT alone, e.g. diagnosing brain lesions and/or the metastasis or recurrence thereof.

In particular, although not exclusively, the present invention may include making a comparison of the uptake of [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]-FACBC uptake in the venous sinus blood pool of the brain and also a comparison of a standardized uptake value (SUV) of the [¹⁸F]-FACBC uptake in a potential lesion against a reference threshold standardized uptake value (SUV)threshoid. Typically, these comparisons may allow for a more accurate diagnosis of the lesion than using MRI and/or CT alone, e.g. diagnosing brain lesions and/or the metastasis or recurrence thereof.

In accordance with a first aspect, the present invention provides a method of using [¹⁸F]-FACBC, comprising the steps of:

(a) administering a detectable amount of [¹⁸F]-FACBC to a subject;

(b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject;

(c) analysing the one or more PET scan images by: (i) comparing [¹⁸F]-FACBC uptake in a potential lesion of the head region of the subject against [¹⁸F]-FACBC uptake in the venous sinus blood pool of the head region; or, (ii) comparing a standardized uptake value (SUV) of the [¹⁸F]- FACBC uptake in a potential lesion against a reference threshold standardized uptake value (SUV)threshoid; or (iii) a combination of steps (i) and (ii); and

(d) determining whether the potential lesion is a brain lesion based on the analysis of step (c).

The method of the first aspect may be further used to diagnose a brain lesion, such as a metastatic brain lesion, in a subject. For example, the brain lesion may comprise a cancer lesion, such as a metastatic cancer lesion.

The method of the first aspect may be further used to distinguish between metastatic cancer, particularly recurrent metastatic cancer, in the brain and treatment-related changes in the brain, such as radiation necrosis and pseudo-progression.

However, and for the avoidance of doubt, the method of the first aspect may be used for nondiagnostic purposes.

Accordingly, the present invention, as defined and identified herein, may be used for diagnosing a brain lesion, such as a metastatic cancer lesion in the brain, of a subject.The present invention, as defined and identified herein, provides a method of imaging which typically allows for reproducible, reliable imaging for detection and monitoring of metastatic cancer in the brain of a subject. The present invention, as defined herein, typically provides a reproducible and reliable method to distinguish between metastatic cancer in the brain and disease recurrence and an artefact(s) of treatment-related changes in the brain, such as radiation necrosis and pseudoprogression.

Suitably, references to in-vivo diagnosis method(s) of the present invention are also to be interpreted as references to compounds, diagnostic compositions and medicaments of the invention for use in said method(s) of diagnosis.

An exemplary embodiment of the first aspect of the invention comprises: step (c)(i) comparing [¹⁸F]-FACBC uptake in a potential lesion of the head region of the subject against [¹⁸F]-FACBC uptake in the venous sinus (i.e. venous sinus blood pool) of the head region; and, step (d) determining whether the potential lesion is a brain lesion.

For example, it has been found that if the amount of [¹⁸F]-FACBC uptake in the potential lesion is greater than the amount of [¹⁸F]-FACBC uptake in the venous sinus (i.e. venous sinus blood pool) of the head region, then the potential lesion is identifiable as a brain lesion, especially a brain cancer lesion, more especially a metastatic cancer brain lesion.

For example, it has been found that if the amount of [¹⁸F]-FACBC uptake in the potential lesion is less than the amount of [¹⁸F]-FACBC uptake in the venous sinus (i.e. venous sinus blood pool) of the head region, then the potential lesion is typically not a brain lesion but may be an artefact of treatment-related changes, such as radiation necrosis and pseudo-progression.

For example, the comparison of [¹⁸F]-FACBC uptake in the potential lesion against [¹⁸F]-FACBC against uptake in the venous sinus of the head region may be performed by visually comparing the one or more positron emission tomography (PET) scan images of the respective potential lesion against the venous sinus of the subject. Typically, a region having a greater amount of [¹⁸F]- FACBC uptake exhibits an increased intensity in the PET scan image compared with a region having a lower amount of [¹⁸F]-FACBC uptake. Further, such a visual comparison of different parts of one or more PET scan image(s) is routine practice to those skilled in the art, for example a clinician.

For example, step (c)(i) comparing [¹⁸F]-FACBC uptake in a potential lesion of the head region of the subject against [¹⁸F]-FACBC uptake in the venous sinus (i.e. venous sinus blood pool) of the head region preferably includes the step of making a visual comparison of the positron emission tomography (PET) scan image(s) of the potential lesion against the venous sinus.

Accordingly, step (d) may include the further step of identifying the potential lesion as a brain lesion, especially a metastatic cancer lesion or recurrence thereof, when the PET scan image of the potential lesion exhibits greater intensity compared with the PET scan image of the venous sinus. Accordingly, step (d) may include the further step of identifying the potential lesion as not a brain lesion, when the PET scan image of the potential lesion exhibits lower intensity compared with the PET scan image of the venous sinus.

A visual comparison of the intensity of the PET scan image of the entire potential lesion may be made against the intensity of the PET scan image of the entire venous sinus.

An alternative exemplary embodiment of the first aspect of the invention comprises step: (c)(ii) comparing the maximum standardized uptake value (SUV)_max of the [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold maximum standardized uptake value (SUV) thresholdmax, wherein said reference threshold maximum standardized uptake value (SUV)threshoid-max is a numerical value of 4.0 to 4.1, and step (d) includes determining if the potential lesion is a brain lesion.

For example, it has been found that if the (SUV)_max of [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to the reference threshold maximum standardized uptake value (SUV)threshoid-max, as defined and identified herein, then the potential lesion is identifiable as a brain lesion, especially a brain cancer lesion, more especially a metastatic cancer brain lesion.

For example, it has been found that if the (SUV)_max of [¹⁸F]-FACBC uptake in the potential lesion is less than the reference threshold maximum standardized uptake value (SUV)threshoid-max, as defined and identified herein, then the potential lesion is typically not a brain lesion but may be an artefact of treatment-related changes such as radiation necrosis and pseudo-progression.

For example, the reference threshold maximum standardized uptake value (SUV)threshoid-max is a numerical value of 4.1 to 4.2, such as 4.2 to 4.3 such as 4.3 to 4.4, such as 4.4 to 4.5, such as 4.5 to 4.6, such as 4.6 to 4.7, such as 4.7 to 4.8, such as 4.8 to 4.9, or such as 4.9 to 5.0.

For example, a preferred reference threshold maximum standardized uptake value (SUV)threshoid- max is a numerical value of 4.5 to 4.6, such as 4.6 to 4.7, such as 4.7 to 4.8, such as 4.8 to 4.9, or such as 4.9 to 5.0. The reference threshold maximum standardized uptake value (SUV)threshoid-max is typically a numerical value of less than or equal to 6.0.

For example, the reference threshold maximum standardized uptake value (SUV)threshoid-max is a numerical value within the range of 4.0 to 6.0, such as 4.1 to 6.0, such as 4.2 to 6.0, such as 4.3 to 6.0, such as 4.4 to 6.0, such as 4.5 to 6.0 such as 4.6 to 6.0, such as 4.5 to 5.9 such as 4.6 to 5.9, such as 4.5 to 5.8 such as 4.6 to 5.8, such as 4.5 to 5.7 such as 4.6 to 5.7, such as 4.5 to 5.6 such as 4.6 to 5.6, such as 4.5 to 5.5 such as 4.6 to 5.5, such as 4.5 to 5.4 such as 4.6 to 5.4, such as 4.5 to 5.3 such as 4.6 to 5.3, such as 4.5 to 5.2 such as 4.6 to 5.2, such as 4.5 to 5.1 such as 4.6 to 5.1, such as 4.5 to 5.0 such as 4.6 to 5.0.

A further alternative exemplary embodiment of the first aspect of the invention comprises step: (c)(ii) comparing the peak standardized uptake value (SUV)_peak of the [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold peak standardized uptake value (SUV)threshoid-peak, wherein said reference threshold peak standardized uptake value (SUV) threshold-peak is a numerical value of 2.0 to 2.1, and step (d) includes determining if the potential lesion is a brain lesion.

For example, it has been found that if the (SUV)_peak of [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to the reference threshold peak standardized uptake value (SUV)threshoid-peak, as defined and identified herein, then the potential lesion is identifiable as a brain lesion, , especially a brain cancer lesion, more especially a metastatic cancer brain lesion.

For example, it has been found that if the (SUV)_peak of [¹⁸F]-FACBC uptake in the potential lesion is less than the reference threshold peak standardized uptake value (SUV)threshoid-peak, as defined and identified herein, then the potential lesion is typically not a brain lesion but may be an artefact of treatment-related changes such as radiation necrosis and pseudo-progression.

For example, the reference threshold peak standardized uptake value (SUV)threshoid-peak is a numerical value of 2.1 to 2.2, such as 2.2 to 2.3, such as 2.3 to 2.4, such as 2.4 to 2.5, such as 2.5 to 2.6, such as 2.6 to 2.7, such as 2.7 to 2.8, such as 2.8 to 2.9, such as 2.9 to 3.0, such as 3.0 to 3.1, such as 3.1 to 3.2, such as 3.2 to 3.3, such as 3.3 to 3.4, such as 3.4 to 3.5, such as 3.5 to 3.6, such as 3.6 to 3.7, such as 3.7 to 3.8, such as 3.8 to 3.9, or such as 3.9 to 4.0.

For example, a preferred reference threshold peak standardized uptake value (SUV)threshoid-peak is a numerical value of 3.0 to 3.1, such as 3.1 to 3.2, such as 3.2 to 3.3, such as 3.3 to 3.4, such as 3.4 to 3.5, such as 3.5 to 3.6, such as 3.6 to 3.7

The reference threshold peak standardized uptake value (SUV) threshold-peak is typically a numerical value of less than or equal to 6.0.

For example, the reference threshold peak standardized uptake value (SUV)threshoid-peak is a numerical value within the range of 2.0 to 6.0, such as 2.1 to 5.5, such as 2.2 to 5.0, such as 2.3 to 5.0, such as 2.4 to 5.0, such as 2.5 to 5.0, such as 2.5 to 4.5, such as 2.5 to 4.0, such as 2.6 to 4.0, such as 2.7 to 4.0, such as 2.8 to 4.0, such as 2.9 to 4.0, such as 3.0 to 4.0, such as 3.0 to 3.9, such as 3.0 to 3.8.

A further example of the first aspect of the invention comprises: step (c)(i) comparing [¹⁸F]- FACBC uptake in a potential lesion of the head region of the subject against [¹⁸F]-FACBC uptake in the venous sinus (i.e. venous sinus blood pool) of the head region, as defined and identified herein; and, step (c)(ii) comparing the maximum standardized uptake value (SUV)_max of the [¹⁸F]- FACBC uptake in the potential lesion against a reference threshold maximum standardized uptake value (SUV)threshoid-max, wherein said reference threshold maximum standardized uptake value (SUV)threshoid-max is a numerical value of 4.0 to 4.1, and as further identified and defined herein; and, step (d) determining if the potential lesion is a brain lesion.

For example, it has been found that if the amount of [¹⁸F]-FACBC uptake in the potential lesion is greater than the amount of [¹⁸F]-FACBC uptake in the venous sinus, and also the (SUV)_max of [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to the reference threshold maximum standardized uptake value (SUV)threshoid-max, as defined and identified herein, then the potential lesion is identifiable as a brain lesion, especially a brain cancer lesion, more especially a metastatic cancer brain lesion. A further example of the first aspect of the invention comprises: step (c)(i) comparing [¹⁸F]- FACBC uptake in a potential lesion of the head region of the subject against [¹⁸F]-FACBC uptake in the venous sinus (i.e. venous sinus blood pool) of the head region, as identified and defined herein; and, step (c)(ii) comparing the peak standardized uptake value (SUV)_peak of the [¹⁸F]- FACBC uptake in the potential lesion against a reference threshold peak standardized uptake value (SUV)threshoid-peak, wherein said reference threshold peak standardized uptake value (SUV)threshoid- peak is in the range of 2.0 to 2.1, and as further identified and defined herein; and, step (d) determining if the potential lesion is a brain lesion.

For example, it has been found that if the amount of [¹⁸F]-FACBC uptake in the potential lesion is greater than the amount of [¹⁸F]-FACBC uptake in the venous sinus, and also the (SUV)_peak of [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to the reference threshold peak standardized uptake value (SUV)threshoid-peak, as defined and identified herein, then the potential lesion is identifiable as a brain lesion, especially a brain cancer lesion, more especially a metastatic cancer brain lesion.

In accordance with a second aspect, the present invention provides [¹⁸F]-FACBC for use in determining whether a potential lesion of the head region of a subject is a brain lesion, as defined in accordance with the first aspect, comprising the steps of: (a) administering a detectable amount of [¹⁸F]-FACBC to a subject; (b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject; (c) analysing the one or more PET scan images by: (i) comparing [¹⁸F]-FACBC uptake in a potential lesion of the head region of the subject against [ ¹⁸F] - FACBC uptake in venous sinus (i.e. venous sinus blood pool) of the head region, as defined in accordance with the first aspect; or, (ii) comparing a standardized uptake value (SUV) of the [¹⁸F]- FACBC uptake in a potential lesion against a reference threshold standardized uptake value (SUV)threshoid, as defined and identified in accordance with the first aspect; or (iii) a combination of steps (i) and (ii); and, (d) determining whether the potential lesion is a brain lesion, as defined in accordance with the first aspect, based on the analysis of step (c). For example, the second aspect of the present invention provides [¹⁸F]-FACBC for use in diagnosing a brain lesion, such as a metastatic brain lesion, in a subject. For example, the brain lesion comprises a cancer lesion, such as a metastatic cancer lesion.

For example, the second aspect of the present invention provides [¹⁸F]-FACBC for use to distinguish between metastatic cancer, such as recurrent metastatic cancer, in the brain and treatment-related changes in the brain, such as radiation necrosis and pseudo-progression.

For example, the [¹⁸F]-FACBC may be in the form of a diagnostically acceptable composition for administration to a subject (e.g., a patient).

In a third aspect of the invention, there is provided a method of using [¹⁸F]-FACBC (e.g., for diagnosing brain lesions) in a subject comprising the steps of:

(a) administering a detectable amount of [¹⁸F]-FACBC to the subject, e.g., administering an amount of [¹⁸F]-FACBC to the subject that is detectable by imaging;

(b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject, the head region including parotid glands and a blood pool;

(c) comparing [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]-FACBC uptake in the blood pool and/or the parotid glands, e.g., analysing the one or more PET scan images by comparing [¹⁸F]-FACBC uptake in the potential lesion against [¹⁸F]-FACBC uptake in the blood pool of the head region, or the parotid glands, or both the blood pool and the parotid glands; and

In a fourth aspect of the invention, there is provided a method of using [¹⁸F]-FACBC, e.g., for diagnosing a brain lesion in a subject, the method comprising the steps of: a) administering a detectable amount of [¹⁸F]-FACBC to the subject; b) acquiring one or more positron emission tomography (PET) scan images of head region of the subject; c) comparing [¹⁸F]-FACBC uptake in a potential lesion against [18F]-FACBC uptake in the blood pool and/or the parotid glands, e.g., analysing the one or more PET scan images by comparing [¹⁸F]-FACBC uptake in the potential lesion against [¹⁸F]-FACBC uptake in the blood pool of the head region, the parotid glands, or both the blood pool and the parotid glands; wherein the subject is instructed to consume no food or calorie-containing drink during a period of time prior to the administration of [¹⁸F]-FACBC, e.g., wherein the subject has followed instructions to consume no food or calorie-containing drink during a period of time prior to the administration of the [¹⁸F]-FACBC; and d) determining whether the potential lesion is a brain lesion based on the analysis of step c).

The blood pool, e.g., according to the third and fourth aspect of the invention, may represent the venous sinus blood pool.

Suitably, it should be appreciated, that exemplary feature(s) of a particular aspect of the present invention may each independently represent feature(s) of another aspect of the invention. Accordingly, feature(s) of the one aspect of the invention may independently represent features of another aspect of the invention.

The methods herein may include, for example, instructions for the subject to consume no food or calorie-containing drink during a period of time prior to the administration of the [¹⁸F]-FACBC, the subject having followed the instructions. The period of time may be, e.g., at least 4 hours (e.g., 4 continuous hours) or at least 6 hours (e.g., 6 continuous hours) prior to the administration of the [¹⁸F]-FACBC.

For example, for a period of time prior to the administration of the [¹⁸F]-FACBC to a subject, step (a) in each and every aspect of the invention, the subject may consume no food or caloriecontaining drink, for example, consume no food or calorie-containing drink for a period of 4 hours, such as 6, hours, e.g. continuous hours.

For example, acquiring the PET scan image(s), step (b) in each and every aspect of the invention, may start 8 to 12 minutes after the administration of the [¹⁸F]-FACBC to a subject, e.g., 10 minutes after the administration of the [¹⁸F]-FACBC. The [¹⁸F]-FACBC may be administered as an intravenous bolus injection.

The [¹⁸F]-FACBC may be administered to a subject in an effective detectable amount (e.g. administering an amount of [¹⁸F]-FACBC to the subject that is detectable by PET imaging). An exemplary detectable amount of [¹⁸F]-FACBC is 185 ± 20% MBq, according to some aspects herein.

Potential lesion [¹⁸F]-FACBC uptake (that is, uptake of [¹⁸F]-FACBC by the potential lesion) which is higher than [¹⁸F]-FACBC uptake in reference structures, e.g., venous sinus, may be indicative of the presence of brain lesions, e.g., indicative of the potential lesion being a brain lesion. For example, the [¹⁸F]-FACBC uptake in the potential lesion may be higher than the [¹⁸F]- FACBC uptake in the venous sinus (i.e. venous sinus blood pool), and step d) includes determining that the potential lesion is a brain lesion. The brain lesion may be a cancer lesion, e.g., a metastatic cancer lesion. In some examples, the potential lesion may be suspicious for a recurrence of cancer in the subject. In at least one example, the [¹⁸F]-FACBC uptake in the potential lesion is lower than or equal to the [¹⁸F]-FACBC uptake in the venous sinus (i.e. venous sinus blood pool), and step d) includes determining that the potential lesion is not a brain lesion.

In some examples herein, the one or more PET scan images comprise a first PET scan image and at least one subsequent PET scan image, wherein analysing the one or more PET scan images in step c) comprises comparing intensities of [¹⁸F]-FACBC uptake in the first PET scan image and the at least one subsequent PET scan image to determine whether the intensity of [¹⁸F]-FACBC uptake in the at least one subsequent PET scan image has increased, remained constant, or decreased relative to the intensity of [¹⁸F]-FACBC uptake of the first PET scan image.

In some examples herein, the one or more PET scan images comprises a PET scan image at a first location and at least one PET scan image at a subsequent location, and wherein analysing the one or more PET scan images in step c) comprises comparing intensities of [¹⁸F]-FACBC uptake in the PET scan image at the first location and of [¹⁸F]-FACBC uptake in the at least one PET scan image at the subsequent location to determine whether the intensity of the [¹⁸F]-FACBC uptake in the at least one PET scan image at the subsequent location has increased, remained constant, or decreased relative to the intensity of the [¹⁸F]-FACBC uptake in the PET scan image at the first location.

An increase in the relative intensity of [¹⁸F]-FACBC uptake in said at least one subsequent PET scan image relative to the intensity of [¹⁸F]-FACBC uptake of the first PET scan image for a potential lesion, such as a lesion identifiable as a brain cancer lesion according to any aspect of the invention, may be indicative of recurrent brain cancer, such as recurrent metastatic brain cancer.

For example, [¹⁸F]-FACBC uptake in the potential lesion which is greater than the [18F]-FACBC uptake in the parotid glands and/or venous sinus blood pool may be indicative of the presence of the brain lesion, e.g., indicative of the potential lesion being a brain lesion.

In some embodiments, the potential lesion is a brain lesion that contains diseased tissue and may be a cancer lesion, for example a metastatic cancer lesion.

Diagnosis of a brain lesion, for example a metastatic cancer lesion, may be performed where the potential lesion [¹⁸F]-FACBC uptake (that is, uptake of [¹⁸F]-FACBC by the potential lesion) is greater than [¹⁸F]-FACBC uptake in the venous sinus.

Diagnosis of the absence of a brain lesion, for example a metastatic cancer lesion, may be performed where the potential lesion [¹⁸F]-FACBC uptake (that is, uptake of [¹⁸F]-FACBC by the potential lesion) is less than [¹⁸F]-FACBC uptake in the venous sinus.

Diagnosis of a brain lesion, for example a metastatic cancer lesion, may be performed where the maximum standardized uptake value (SUV)_max of the [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to a reference threshold maximum standard uptake value (SUV)threshoid-max, as defined and identified herein, especially greater than or equal to a reference threshold maximum standard uptake value (SUV)threshoid-max of 4.0 to 4.1. For diagnosing a brain lesion the reference threshold maximum standardized uptake value (SUV)threshoid-max of the [¹⁸F]-FACBC uptake in the potential lesion may be as defined herein.

Diagnosis of a brain lesion, for example a metastatic cancer lesion, may be performed where the maximum standardized uptake value (SUV)_max of the [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to a reference threshold maximum standard uptake value (SUV)threshoid-max and the reference threshold maximum standardized uptake value (SUV)threshoid-max is a numerical value of 4.0 to 4.1, such as 4.1 to 4.2, such as 4.2 to 4.3, such as 4.3 to 4.4, such as 4.4 to 4.5, such as 4.5 to 4.6, such as 4.6 to 4.7, such as 4.7 to 4.8, such as 4.8 to 4.9, or such as 4.9 to 5.0.

Diagnosis of the absence of a brain lesion, for example a metastatic cancer lesion, may be performed where the maximum standardized uptake value (SUV)_max of the [¹⁸F]-FACBC uptake in the potential lesion is less than said reference threshold maximum standard uptake value (SUV)threshoid-max, as defined herein.

Diagnosis of a brain lesion, for example a metastatic cancer lesion, may be performed where the peak standardized uptake value (SUV)_peak of the [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to a reference threshold peak standard uptake value (SUV)threshoid-peak, as defined herein, especially greater than or equal to a reference threshold peak standard uptake value (SUV)threshold-peak Of 2.0 to 2.1.

For diagnosing a brain lesion the reference threshold peak standardized uptake value (SUV)threshoid- peak of the [¹⁸F]-FACBC uptake in the potential lesion may be as defined herein.

Diagnosis of a brain lesion, for example a metastatic cancer lesion, may be performed where the peak standardized uptake value (SUV)_peak of the [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to a reference threshold peak standard uptake value (SUV)threshoid-peak and the reference threshold peak standardized uptake value (SUV)threshoid-peakis a numerical value of 3.0 to 3.1, such as 3.1 to 3.2, such as 3.2 to 3.3, such as 3.3 to 3.4, such as 3.4 to 3.5, such as 3.5 to 3.6, such as 3.6 to 3.7. Diagnosis of the absence of a brain lesion, for example a metastatic cancer lesion, may be performed where the peak standardized uptake value (SUV)_peakof the [¹⁸F]-FACBC uptake in the potential lesion is less than said reference threshold peak standard uptake value (SUV)threshoid-peak, as defined herein.

Diagnosis of a brain lesion, for example a metastatic cancer lesion, may be performed where both (i) the potential lesion [¹⁸F]-FACBC uptake (that is, uptake of [¹⁸F]-FACBC by the potential lesion) is greater than [¹⁸F]-FACBC uptake in the venous sinus (i.e. venous sinus blood pool), and also (ii) the maximum standardized uptake value (SUV)_max of the [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to a reference threshold maximum standard uptake value (SUV)threshoid-max, as defined herein, especially greater than or equal to a reference threshold maximum standard uptake value (SUV)threshoid-max of 4.0 to 4.1.

Diagnosis of a brain lesion, for example a metastatic cancer lesion, may be performed where both (i) the potential lesion [¹⁸F]-FACBC uptake (that is, uptake of [¹⁸F]-FACBC by the potential lesion) is higher than [¹⁸F]-FACBC uptake in the venous sinus (i.e. venous sinus blood pool), and also (ii) the peak standardized uptake value (SUV)_peak of the [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to a reference threshold peak standard uptake value (SUV)threshoid- _peak, as defined herein, especially greater than or equal to a reference threshold maximum standard uptake value (SUV)threshoid-_Peak of 2.0 to 2.1.

Diagnosis of a brain lesion, for example a metastatic cancer lesion, may be performed where the potential lesion [¹⁸F]-FACBC uptake (that is, uptake of [¹⁸F]-FACBC by the potential lesion) is higher than parotid glands [¹⁸F]-FACBC uptake.

Diagnosis of a brain lesion, for example a metastatic cancer lesion may be performed where the potential lesion [¹⁸F]-FACBC uptake is higher than blood pool [¹⁸F]-FACBC uptake, such as venous sinus blood pool uptake.

Diagnosis of a brain lesion, for example a metastatic cancer lesion, may be performed where the potential lesion [¹⁸F]-FACBC uptake is higher than both blood pool [¹⁸F]-FACBC uptake and parotid glands [¹⁸F]-FACBC uptake. An exemplary blood pool represents the venous sinus blood pool. Diagnosis of the absence of a brain lesion, for example a metastatic cancer lesion may be performed where the potential lesion [¹⁸F]-FACBC uptake is not higher than blood pool [¹⁸F]- FACBC uptake. An exmplary blood pool represents the venous sinus blood pool.

In some embodiments of the present disclosure, the potential lesion [¹⁸F]-FACBC uptake is visually compared to [¹⁸F]-FACBC activity in the blood pool and/or parotid glands to analyse and determine whether the potential lesion is a metastatic brain lesion in order to diagnose brain metastasis. An exemplary blood pool represents the venous sinus blood pool.

In some embodiments of the present disclosure, [¹⁸F]-FACBC uptake higher than the blood pool is considered as suspicious for brain metastasis. An exemplary blood pool represents the venous sinus blood pool.

In some embodiments of the present disclosure, [¹⁸F]-FACBC uptake similar or less than blood pool is considered as non-suspicious for brain metastasis, e.g., indicative that the potential lesion is not a metastatic brain lesion. An exemplary blood pool represents the venous sinus blood pool..

According to a further aspect of the invention, there is provided a kit for imaging, diagnosing or monitoring metastatic cancer, comprising: a) [¹⁸F]-FACBC tracer; and b) administration instructions according to any of the aspects described above and/or elsewhere herein.

According to a further aspect of the invention, there is provided the acquisition of images using a PET/MRI or PET/CT scanner. The simultaneous or consecutive acquisition of images on a PET/MRI or PET/CT scanner may offer improved diagnostic accuracy over the generation of images on separate PET and MRI instruments or on separate PET and CT instruments. The conjoint use with MRI may improve the localisation of lesions, particularly where the lesions are small, for example in the case of metastatic lesions. The method of administration can be the methods described herein. Definitions

In this specification, the following words and expressions, if and when used, shall have the meanings ascribed below: singular forms “a,” “an,” and “the” include plural reference unless the context dictates otherwise;

“approximately” and “about” refer to being nearly the same as a referenced number or value (e.g. substantially the same as without affecting the material aspect(s) of the invention). The terms “approximately” and “about” generally should be understood to encompass ± 5% of a specified amount or value;

“comprising” or any cognate word specifies the presence of stated features, steps, or integers or components, but does not preclude the presence or addition of one or more other features, steps, integers, components or groups thereof. The expressions “consists of’ or “consists essentially of’ or cognates may be embraced within “comprises” or any cognate word. The expression “consists essentially of’ permits inclusion of substances not materially affecting the characteristics of the composition to which it applies. The expression “consists of’ or cognates means only the stated features, steps, integers components or groups thereof are present to which the expression refers;

“detectable effective amount” in respect of the amount of [¹⁸F]-FACBC administered to a subject means an amount of [¹⁸F]-FACBC, preferably administered by intravenous administration, that is effective to provide, and provides, uptake by a potential lesion to allow acquisition of a PET image of the potential lesion. An exemplary detectable amount of [¹⁸F]-FACBC is 185MBq (mega bequerels) ± 20%;

“standardised uptake value (SUV)” in respect of uptake of [¹⁸F]-FACBC by a potential lesion or other region (e.g. venous sinus and/or parotid glands) of the head represents the value obtained from the ratio of the decay corrected amount of radioactivity uptake by the potential lesion (or uptake by the other region of interest) in the head, typically measured in Bq/ml, to the total amount of radioactivity administered to a subject, typically measured in Bq, multiplied by the body weight of the subject, typically measured in grams;

“maximum standardised uptake value (SUV)_max” in respect of uptake of [¹⁸F]-FACBC by a potential lesion or other region (e.g. venous sinus) of the head is defined as the standardised uptake value (SUV) measured at a point in the potential lesion (or other region) of the head, respectively, where maximum uptake of [¹⁸F]-FACBC occurs. The point where maximum uptake of [¹⁸F]- FACBC occurs in the potential lesion (or other region) of the head represents the highest intensity point (“hottest spot”) in the PET image for the potential lesion or other region. Suitably, (SUV)_max corresponds to (SUV) at the hottest spot in the PET image;

“peak standardised uptake value (SUV)_peak” in respect of uptake of [¹⁸F]-FACBC by a potential lesion or other region (e.g. venous sinus) of the head is defined as the mean standardised uptake value (SUV) in a 1 cm³ spherical volume which sphere is centred on the point where maximum uptake of [¹⁸F]-FACBC occurs in the potential lesion (or other region), i.e. centred on the point in the potential lesion (or other region) where (SUV)_max occurs and is measured;

“mean standardized uptake value (SUV)mean” represents the average standardized uptake value of [¹⁸F]-FACBC within a defined volume of a potential lesion or other region (e.g. venous sinus) of the head;

“reference threshold maximum standardized uptake value (SUV)threshoid-max” represents the lower, including lowest, limit maximum standardized uptake value of a potential lesion such that a potential lesion in the head having a measured maximum standardized uptake value (SUV)_max greater than or equal to reference threshold maximum standardized uptake value (SUV)threshoid-max is identifiable as a brain lesion;

“reference threshold peak standardized uptake value (SUV)threshoid-peak” represents the lower, including lowest, limit peak standardized uptake value of a potential lesion such that a potential lesion in the head having a measured peak standardized uptake value (SUV)_peak greater than or equal to reference threshold peak standardized uptake value (SUV)threshoid-peak is identifiable as a brain lesion;

“standardised uptake value (SUV)”, “maximum standardised uptake value (SUV)max”, “peak standardised uptake value (SUV)_peak”, and “mean standardized uptake value (SUV)mean” of a radiotracer represent known parameters to those skilled in the art and can be measured quantitatively using standard functionality of commercially available PET imaging workstations, e.g. by placing a region/volume-of-interest tool on the potential lesion (or other region of the head), which then calculates the (SUV), (SUV)_max, (SUV)_peak”, and (SUV)mean values;

“commercially available standard PET imaging workstations” includes MIM® software, HERMIA (Hermes Medical Solutions), GE Healthcare Advantage Workstation and Siemens Healthcare;

“venous sinus” means venous sinus blood pool, namely the blood pool of the entire venous sinus region.

Further, it is understood that any upper and lower quantity, range and ratio limits set forth herein may be independently combined. Accordingly, any upper and lower quantity, range and ratio limits set forth herein associated with a particular technical feature of the present invention may be independently combined with any upper and lower quantity, range and ratio limits set forth herein associated with one or more other particular technical feature(s) of the present invention. Furthermore, any particular technical feature of the present invention, and all preferred variants thereof, may be independently combined with any other particular technical feature(s), and all preferred variants thereof, irrespective of whether such features are presented as preferred or not.

Also, it will be understood that the preferred features of each aspect of the present invention are regarded as preferred features of each and every aspect of the present invention.

DETAILED DESCRIPTION OF THE INVENTION The features of the invention relating, where appropriate to each and all aspects of the invention, will now be described in more detail as follows.

Brief Description of Drawings

Figures 1 show representative axial, sagittal and coronal [¹⁸F]-FACBC PET and fused PET/MRI images of the brain. Figure 1 illustrates with arrows, the level of [¹⁸F]-FACBC activity within the blood pool (i.e. venous sinus blood pool), for comparison against [¹⁸F]-FACBC uptake in a potential lesion. Figure lb illustrates with arrows, the level of [¹⁸F]-FACBC activity within the parotid glands, for comparison against [¹⁸F]-FACBC uptake in a potential lesion.

Figure 2 shows representative coronal [¹⁸F]-FACBC PET and fused PET/MRI images of the brain. Upper arrow indicates [¹⁸F]-FACBC uptake in a potential lesion, higher than the level of [¹⁸F]- FACBC activity within the parotid glands (lower arrows).

Figure 3 shows [¹⁸F]-FACBC PET and PET images of the brain. Figure 3a represents an axial image of the brain and illustrates an amount of [¹⁸F]-FACBC uptake in a potential lesion (arrow labelled as PL) greater than the amount of [¹⁸F]-FACBC uptake in the venous sinus blood pool (arrow labelled as VS). Figure 3b represents coronal image of the brain and illustrates [¹⁸F]- FACBC uptake in the venous sinus blood pool (arrows labelled as VS).

Fluciclovine (¹⁸F) injection, also known as [¹⁸F]-FACBC, FACBC, or anti-l-amino-3-¹⁸F- fluorocyclobutane-1 -carboxylic acid, is a synthetic amino acid imaging agent which is taken up specifically by amino acid transporters and is used for positron emission tomography (PET). PET is uniquely suited to evaluate metabolic activity in human tissue for diagnostic imaging purposes. Use of ¹⁸F-fluciclovine in the imaging of brain metastases is of considerable clinical relevance. ¹⁸F-Fluciclovine has utility in the evaluation of primary and metastatic cancers in the brain due at least in part to its low normal brain background uptake and increased uptake by brain tumors. The present inventors have established a protocol which allows for the imaging of brain lesions, e.g., providing greater reliability and reproducibility, allowing the data from PET scan images to be analysed and compared in order to accurately diagnose or monitor brain lesions.

In one aspect of the present disclosure, visual comparison of the uptake of [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]-FACBC uptake in the blood pool and/or the parotid glands allows a more accurate diagnosis of the lesion than using MRI and/or CT alone. Suitably, blood pool represents venous sinus blood pool.

In a further aspect of the present disclosure, visual comparison of the uptake of [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]-FACBC uptake in the venous sinus (i.e. venous sinus blood pool) of the brain allows a more accurate diagnosis of the lesion than using MRI and/or CT alone.

It had previously been reported that an apparent greater uptake of a radiolabelled tracer may often not be sufficient to determine accurately whether an area suspicious for cancer is indeed a brain lesion. For example, studies by Bogsrud et al. (2019) have reported greater uptake by tumours compared to normal brain tissue, but the authors recognized limitations in accuracy based on tumour size and contrast. Advantageously, the present disclosure, which includes comparisons relative to blood pool (i.e. venous sinus blood pool) and/or parotid glands can provide for more accurate analyses of potential lesions to determine whether the potential lesions are indeed brain lesions, e.g. cancerous lesions, especially metastatic brain lesions. In particular, a comparison of [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]-FACBC uptake in the venous sinus using PET image(s) has been found to provide a significantly more accurate and reproducible analysis of potential lesion(s) to determine whether the potential lesion(s) is a brain lesion, particularly a metastatic cancer lesion.

A potential lesion may include, for example, features on a CT or MRI scan image which are not conclusive on whether the features represent a brain lesion containing diseased tissue. In particular, it is typically difficult to differentiate on a CT or MRI scan image those features which represent a brain lesion, especially a metastatic brain lesion, and treatment related changes, such as, radiation necrosis and pseudo-progression. Humans have two parotid glands located on either side of the mouth that are used for salivation. Prior reports using [¹⁸F]-FACBC in imaging have not investigated comparisons relative to parotid glands or relative to blood pool or venous sinus. As further described below, the methods according to the present disclosure using blood pool and/or parotid glands and/or venous sinus as a background reference can provide for more accurate diagnoses of the presence of a brain lesion, e.g., a cancerous brain lesion, such as a malignant or metastatic brain lesion. Suitably, visual comparison of the uptake of [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]-FACBC uptake in the parotid glands using PET images may allow for a more accurate diagnosis of the lesion than using MRI and/or CT alone. Suitably, visual comparison of the uptake of [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]-FACBC uptake in the venous sinus using PET images may allow for a more accurate diagnosis of the lesion than using MRI and/or CT alone.

Quantitative comparison of the uptake of [¹⁸F]-FACBC uptake in a potential lesion against a maximum standardized uptake value (SUV)_max threshold of 1 to 5.0 may allow for a more accurate diagnosis of the lesion than using MRI and/or CT alone. Semi-quantitative comparison of the uptake of [¹⁸F]-FACBC uptake in a potential lesion against a peak standardized uptake value (SUV)peak threshold of 1 to 4.0 may allow for a more accurate diagnosis of the lesion than using MRI and/or CT alone. In some embodiments of the present disclosure, the SUVmax threshold is in a range of 1.0 to 5.0.

In some embodiments of the present disclosure, for example, the SUVmax threshold may be in a range of 1.0 to 1.1, 1.1 to 1.2, 1.2 to 1.3, 1.3 to 1.4, 1.4 to 1.5, 1.5 to 1.6, 1.6 to 1.7, 1.7 to 1.8, 1.8 to 1.9, 1.9 to 2.0, 2.0 to 2.1, 2.1 to 2.2, 2.2 to 2.3, 2.3 to 2.4, 2.4 to 2.5, 2.5 to 2.6, 2.6 to 2.7, 2.7 to 2.8, 2.8 to 2.9, 2.9 to 3.0, 3.0 to 3.1, 3.1 to 3.2, 3.2 to 3.3, 3.3 to 3.4, 3.4 to 3.5, 3.5 to 3.6, 3.6 to 3.7, 3.7 to 3.8, 3.8 to 3.9, 3.9 to 4.0, 4.0 to 4.1, 4.1 to 4.2, 4.2 to 4.3, 4.3 to 4.4, 4.4 to 4.5, 4.5 to 4.6, 4.6 to 4.7, 4.7 to 4.8, 4.8 to 4.9, or 4.9 to 5.0. In some embodiments of the present disclosure, the SUVpeak threshold is in a range of 1.0 to 4.0. In some embodiments of the present disclosure, the SUVpeak threshold may be in a range of 1.0 to 1.1, 1.1 to 1.2, 1.2 to 1.3, 1.3 to 1.4, 1.4 to 1.5, 1.5 to 1.6, 1.6 to 1.7, 1.7 to 1.8, 1.8 to 1.9, 1.9 to 2.0, 2.0 to 2.1, 2.1 to 2.2, 2.2 to 2.3, 2.3 to 2.4, 2.4 to 2.5, 2.5 to 2.6, 2.6 to 2.7, 2.7 to 2.8, 2.8 to 2.9, 2.9 to 3.0, 3.0 to 3.1, 3.1 to 3.2, 3.2 to 3.3, 3.3 to 3.4, 3.4 to 3.5, 3.5 to 3.6, 3.6 to 3.7, 3.7 to 3.8, 3.8 to 3.9, or 3.9 to 4.0.

Disclosed is a method of detecting lesions in a subject, e.g., a patient, comprising administering [¹⁸F]-FACBC to the subject and imaging the subject on a PET/MRI or PET/CT or PET scanner to obtain conjoint PET and MRI images or PET and CT images, or PET images only. The lesions may be metastatic lesions. The administration and/or PET imaging methods may be as described below and elsewhere herein.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, e.g., for diagnosing brain lesions, in a subject comprising the steps of: (a) administering a detectable amount of [¹⁸F]-FACBC to the subject; (b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject; (c) comparing [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]- FACBC uptake in the blood pool and/or the parotid glands; and, (d) determining whether the potential lesion is a brain lesion based on the analysis of step c); wherein potential lesion [¹⁸F]- FACBC uptake which is higher than blood pool and/or parotid glands [¹⁸F]-FACBC uptake is indicative of the presence of one or more brain lesions.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, e.g., for diagnosing a brain lesion, in a subject, comprising the steps of: (a) administering a detectable amount of [¹⁸F]- FACBC to the subject; (b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject; (c) comparing [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]-FACBC uptake in the blood pool and/or the parotid glands; and, (d) determining whether the potential lesion is a brain lesion based on the analysis of step c); wherein the subject is instructed to consume no food or calorie-containing drink during a given period of time prior to the administration of [¹⁸F]-FACBC; and, wherein the [¹⁸F]-FACBC uptake in the potential lesion which is higher than the [¹⁸F]-FACBC uptake in the blood pool and/or the parotid glands is indicative of the presence of the brain lesion.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, e.g., for diagnosing brain lesions, in a subject comprising the steps of: (a) administering a detectable amount of [¹⁸F]-FACBC to the subject; (b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject; (c) comparing [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F] - FACBC uptake in the venous sinus; and, (d) determining whether the potential lesion is a brain lesion based on the analysis of step (c); wherein if the amount of [¹⁸F]-FACBC uptake in the potential lesion is greater than [¹⁸F]-FACBC uptake in the venous sinus is indicative of the presence of one or more brain lesions.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, e.g., for diagnosing a brain lesion, in a subject, comprising the steps of: (a) administering a detectable amount of [¹⁸F]- FACBC to the subject; (b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject; (c) comparing [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]-FACBC uptake in the venous sinus; and, (d) determining whether the potential lesion is a brain lesion based on the analysis of step (c); wherein the subject is instructed to consume no food or calorie-containing drink during a given period of time prior to the administration of [¹⁸F] - FACBC; and, wherein if the amount of [¹⁸F]-FACBC uptake in the potential lesion is greater than the [¹⁸F]-FACBC uptake in the venous sinus is indicative of the presence of the brain lesion.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, comprising the steps of: (a) administering a detectable amount of [¹⁸F]-FACBC to a subject; (b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject; (c) analysing the one or more PET scan images by comparing the maximum standardized uptake value (SUV)_max of the [¹⁸F] -FACBC uptake in the potential lesion against a reference threshold maximum standardized uptake value (SUV)threshoid-max, wherein said reference threshold maximum standardized uptake value (SUV)threshoid-max is a value of 4.0 to 4.1; and, (d) determining whether the potential lesion is a brain lesion based on the analysis of step (c); wherein if the maximum standardized uptake value (SUV)_max of [¹⁸F]-FACBC by the potential lesion is greater than or equal to the reference threshold maximum standardized uptake value (SUV)threshoid-max is indicative of the presence of one or more brain lesions.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, e.g., for diagnosing a brain lesion, in a subject, comprising the steps of: (a) administering a detectable amount of [¹⁸F]- FACBC to the subject; (b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject; (c) analysing the one or more PET scan images by comparing the maximum standardized uptake value (SUV)_max of the [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold maximum standardized uptake value (SUV) thresholdmax, wherein said reference threshold maximum standardized uptake value (SUV)threshoid-max is a value of 4.0 to 4.1; and, (d) determining whether the potential lesion is a brain lesion based on the analysis of step (c); wherein the subject is instructed to consume no food or calorie-containing drink during a given period of time prior to the administration of [¹⁸F]-FACBC; and, wherein if the maximum standardized uptake value (SUV)_max of [¹⁸F]-FACBC by the potential lesion is greater than or equal to the reference threshold maximum standardized uptake value (SUV)threshoid- max is indicative of the presence of one or more brain lesions.

For example, the reference threshold maximum standardized uptake value (SUV)threshoid-max is a value of 4.1 to 4.2, preferably 4.2 to 4.3, more preferably 4.3 to 4.4, such as 4.4 to 4.5, such as 4.5 to 4.6, such as 4.6 to 4.7, such as 4.7 to 4.8, such as 4.8 to 4.9, or such as 4.9 to 5.0.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, comprising the steps of: (a) administering a detectable amount of [¹⁸F]-FACBC to a subject; (b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject; (c) analysing the one or more PET scan images by comparing the peak standardized uptake value (SUV)_peak of the [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold peak standardized uptake value (SUV)threshoid-peak, wherein said reference threshold peak standardized uptake value (SUV)threshoid-peak is a value of 2.0 to 2.1 and, (d) determining whether the potential lesion is a brain lesion based on the analysis of step (c); wherein if the peak standardized uptake value (SUV)_peak of [¹⁸F]-FACBC by the potential lesion is greater than or equal to the reference threshold peak standardized uptake value (SUV)threshoid-peak is indicative of the presence of one or more brain lesions.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, e.g., for diagnosing a brain lesion, in a subject, comprising the steps of: (a) administering a detectable amount of [¹⁸F] - FACBC to the subject; (b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject; (c) analysing the one or more PET scan images by comparing the peak standardized uptake value (SUV)_peak of the [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold peak standardized uptake value (SUV)threshoid-peak, wherein said reference threshold peak standardized uptake value (SUV)threshoid-peakis a value of 2.0 to 2.1; and, (d) determining whether the potential lesion is a brain lesion based on the analysis of step (c); wherein the subject is instructed to consume no food or calorie-containing drink during a given period of time prior to the administration of [¹⁸F]-FACBC; and, wherein if the peak standardized uptake value (SUV)_peak of [¹⁸F]-FACBC by the potential lesion is greater than or equal to the reference threshold maximum standardized uptake value (SUV) threshold-peak is indicative of the presence of one or more brain lesions.

For example, the reference threshold peak standardized uptake value (SUV)threshoid-peakis a value of 3.0 to 3.1, such as 3.1 to 3.2, such as 3.2 to 3.3, such as 3.3 to 3.4, such as 3.4 to 3.5, such as 3.5 to 3.6, such as 3.6 to 3.7.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, comprising the steps of: (a) administering a detectable amount of [¹⁸F]-FACBC to a subject; (b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject; (c) (i) analysing the one or more PET scan images by comparing the peak standardized uptake value (SUV)_peak of the [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold peak standardized uptake value (SUV)threshoid-peak, wherein said reference threshold peak standardized uptake value (SUV)threshoid-peak is a value of 2.0 to 2.1; and, (c)(ii) analysing the one or more PET scan images by comparing the maximum standardized uptake value (SUV)_max of the [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold maximum standardized uptake value (SUV)threshoid-max, wherein said reference threshold maximum standardized uptake value (SUV)threshoid-max is a value of 4.0 to 4.1; (d) determining whether the potential lesion is a brain lesion based on the analysis of step (c); wherein if the peak standardized uptake value (SUV)_peak of [¹⁸F]-FACBC by the potential lesion is greater than or equal to the reference threshold peak standardized uptake value (SUV)threshoid-peak and also if the maximum standardized uptake value (SUV)max of [¹⁸F]-FACBC by the potential lesion is greater than or equal to the reference threshold maximum standardized uptake value (SUV)threshoid-max is indicative of the presence of one or more brain lesions.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, e.g., for diagnosing a brain lesion, in a subject, comprising the steps of: (a) administering a detectable amount of [¹⁸F]- FACBC to the subject; (b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject; (c)(i) analysing the one or more PET scan images by comparing the peak standardized uptake value (SUV)_peak of the [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold peak standardized uptake value (SUV)threshoid-peak, wherein said reference threshold peak standardized uptake value (SUV)threshoid-peakis a value of 2.0 to 2.1 ; (c)(ii) analysing the one or more PET scan images by comparing the maximum standardized uptake value (SUV)_max of the [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold maximum standardized uptake value (SUV)threshoid-max, wherein said reference threshold maximum standardized uptake value (SUV)threshoid-maxis a value of 4.0 to 4.1; and, (d) determining whether the potential lesion is a brain lesion based on the analysis of step (c); wherein the subject is instructed to consume no food or calorie-containing drink during a given period of time prior to the administration of [¹⁸F]-FACBC; and, wherein if peak standardized uptake value (SUV)_peak of [¹⁸F]-FACBC by the potential lesion is greater than or equal to the reference threshold peak standardized uptake value (SUV)threshoid-peak and also if the maximum standardized uptake value (SUV)max of [¹⁸F]-FACBC by the potential lesion is greater than or equal to the reference threshold maximum standardized uptake value (SUV)threshoid-max is indicative of the presence of one or more brain lesions.is indicative of the presence of one or more brain lesions.

In step (a), [¹⁸F]-FACBC may be injected, e.g., as a bolus intravenous injection. The injection can be followed by a saline flush, e.g., a saline flush of about 10 mL or less.

After injection, lesion cells uptake [¹⁸F]-FACBC and the cells which have taken up the tracer can be subsequently visualised. Acquisition can start 8 to 12 minutes after the end of the injection, such as about 10 minutes after the end of the injection. Acquisition can start 8, 9, 10, 11 or 12 minutes after the end of the injection. [¹⁸F]-FACBC is generally taken up by lesion cells quickly compared to other PET radiotracers with different uptake mechanisms. For example, in FDG-PET imaging, acquisition usually starts at least 45 minutes after injection.

A “detectable amount” of [¹⁸F]-FACBC refers to a dosage of [¹⁸F]-FACBC which is taken up by lesion cells allowing those cells to be detected by PET imaging. In some examples, the dosage or detectable amount of [¹⁸F]-FACBC administered to the subject is 185 ± 20% MBq. The dosage may be diluted up to 10 mF, e.g., via dilution with saline solution.

In at least one embodiment of the present disclosure, the subject, e.g., patient, is instructed to fast for a given period of time prior to the administration of [¹⁸F]-FACBC. The term ’’fast” means to consume no calories, e.g., to consume no food or calorie-containing drink. For example, only water, or other non-calorie-containing fluid, may be consumed during the given period of time prior to the administration of [¹⁸F]-FACBC. In some embodiments of the present disclosure, the given period of time is at least 6 hours. In some embodiments of the present disclosure, the given period of time is 4 to 6 hours. In some embodiments of the present disclosure, the given period of time is at least 4 hours. In some embodiments of the present disclosure, the given period of time is about 4 hours.

The PET imaging technique may utilise scanning devices that detect the 511 keV annihilation photons that are emitted after radioactive decay of fluorine- 18. In addition, “micro-PET” scanners that have high spatial resolution can be used for imaging of small animals. In addition to PET scanners, ¹⁸F-radioactivity can also be monitored using one or more radiation detector probes.

In step (b), the acquisition/scanning time can be for 8 to 12 minutes upon the start of acquisition, such as about 10 minutes upon the start of acquisition.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, e.g., for imaging metastatic cancer, in a subject, comprising the steps of: (a) administering to the subject a first dose of [¹⁸F]-FACBC (e.g., a first dose of a detectable amount of [¹⁸F]-FACBC) and allowing time for the [¹⁸F]-FACBC to accumulate at one or more areas of interest within the subject;(b) obtaining a first PET scan image of the subject, e.g., obtaining a first PET scan image of a head region of the subject that includes parotid glands; (c) administering to the subject a second dose of [¹⁸F]-FACBC (e.g., a second dose of a detectable amount of [¹⁸F]-FACBC that is the same or different than the first dose) and allowing time for [¹⁸F]-FACBC to accumulate at the one or more areas of interest within the subject; (d) obtaining a second PET scan image of the subject, e.g., obtaining a second PET scan image of the head region of the subject; (e) comparing [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]-FACBC uptake in the blood pool and/or the parotid glands for the first and second PET scan images, e.g., to determine whether the potential lesion is a brain lesion; wherein the first and second scan images indicate the location and intensity of [¹⁸F]-FACBC and wherein localisation of [¹⁸F]-FACBC indicates the presence of lesion tissue in the subject.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, e.g., for imaging metastatic cancer, in a subject, comprising the steps of: (a) administering to the subject a first dose of [¹⁸F]-FACBC (e.g., a first dose of a detectable amount of [¹⁸F]-FACBC) and allowing time for the [¹⁸F]-FACBC to accumulate at one or more areas of interest within the subject; (b) obtaining a first PET scan image of the subject, e.g., obtaining a first PET scan image of a head region of the subject that includes the venous sinus; (c) administering to the subject a second dose of [¹⁸F]- FACBC (e.g., a second dose of a detectable amount of [¹⁸F]-FACBC that is the same or different than the first dose) and allowing time for [¹⁸F]-FACBC to accumulate at said one or more areas of interest within the subject; (d) obtaining a second PET scan image of the subject, e.g., obtaining a second PET scan image of the head region of the subject; (e) comparing [¹⁸F]-FACBC uptake in a potential lesion against [¹⁸F]-FACBC uptake in the venous sinusfor the first and second PET scan images, e.g., to determine whether the potential lesion is a brain lesion; wherein the first and second scan images indicate the location and intensity of [¹⁸F]-FACBC and wherein localisation of [¹⁸F] - FACBC indicates the presence of lesion tissue in the subject.

In some embodiments, there is provided a method of using [¹⁸F]-FACBC, e.g., for diagnosing or monitoring metastatic cancer, in a subject, comprising the steps of: (a) administering to the subject a first dose of a detectable amount of [¹⁸F]-FACBC and allowing time for the [¹⁸F]-FACBC to accumulate at one or more areas of interest within the subject; (b) obtaining a first PET scan image of the subject, e.g., of a head region of the subject, wherein the first PET scan image indicates the location and intensity of [¹⁸F]-FACBC; (c) administering to the subject a second dose of a detectable amount of [¹⁸F]-FACBC and allowing time for [¹⁸F]-FACBC to accumulate at the one or more areas of interest within the subject; (d) obtaining a second PET scan image of the subject, e.g., of the head region of the subject, wherein the second PET scan image indicates the location and intensity of [¹⁸F]-FACBC; and, (e) comparing the first and second PET scan images to determine whether the location and/or intensity of [¹⁸F]-FACBC has increased, remained constant, or decreased, e.g., to determine whether the subject has metastatic cancer.

In at least one embodiment of the present disclosure, both PET and magnetic resonance imaging (MRI) or x-ray computed tomography (CT) scan images is employed. For example, both PET- MRI or PET-CT images may be acquired in steps (b) and (d) of the above methods using a combined PET-MRI or PET-CT system.

In at least one embodiment, [¹⁸F]-FACBC is administered according to the aspects of the present disclosure discussed above.

The time required for [¹⁸F]-FACBC to accumulate in lesion cells in steps (a) and (c) of the aspects described above may be about 10 minutes or less after [¹⁸F]-FACBC is administered. For example, the time taken for [¹⁸F]-FACBC to accumulate is 8 to 12 minutes, such as about 10 minutes. This therefore may allow image acquisition to start 8 to 12 minutes after administration, e.g., about 10 minutes after [¹⁸F]-FACBC administration.

During the PET scan, the subject, e.g., patient, may be in the supine position, with the head stabilised appropriately. The entire brain, including the cerebellum may be in the field of view. Thus, for example, the PET scan image may include a head region of the subject that includes the parotid glands.

Once data has been collected from the first PET scan, the images can be visualised and used to view the level, volume and/or location of lesion [¹⁸F]-FACBC uptake within the subject. Images are usually visually interpreted by a nuclear medicine physician or radiologist and standardised uptake values (SUVs), such as SUVmax and SUVpeak, as defined herein, may be determined by placing a region/volume-of-interest tool (standard functionality on commercially available imaging workstations) on the lesion, which then calculates the respective SUV(s). SUVmax is higher than SUVpeak for any given PET scan. The SUV is as defined herein and represents the ratio of tissue radioactivity concentration to the administered radiation dose divided by subject body weight.

A combination of the SUVmax and SUVpeak values, as defined herein, can be used when assessing the potential lesion.

The time between acquisition of the first and second PET scan images, i.e. between steps (b) and (d) of the aspects described above, can be as much as one year. In some instances, the time between the first and second PET scans is about 6 months, 5 months, 4 months, 3 months, 2 months, 1 month or even less than about 1 month. It will be appreciated that steps (c) and (d) of the aspects described above can be repeated as many times as necessary in order to obtain multiple scan images which can be used to map the development of a lesion over time.

Once image data has been collected from the second PET scan, the first and second PET scan images can be visualised together and used to view the change in extent and location of [¹⁸F]- FACBC uptake by a potential lesion within the subject, allowing for the diagnosis or monitoring of metastatic brain cancer. For example, if the level of lesion [¹⁸F]-FACBC uptake has increased then the subject may be diagnosed with metastatic cancer. In some embodiments, the second PET scan image can be compared to images of data collected from an earlier PET scan image taken before the first PET scan image, in addition to comparison with the first PET scan image. In addition, any subsequent PET scan images obtained after the second PET scan image can be compared with the first and/or second PET scan images.

By comparing the images from two or more differing time points, the differences in the potential lesion uptake of [¹⁸F]-FACBC can be analysed. Comparisons can involve either qualitative image comparison (e.g. contrast of potential lesion uptake to background) or quantitative indices derived from the imaging or external radiation detection data (e.g. SUVs). The development, progression or reduction of any lesions (or potential lesions) can therefore be monitored and diagnosed accordingly. Suitable treatment can then be determined, for example, targeted administration of localised treatment at the site of the lesion. It will be appreciated that the methods described herein can also be used to monitor response to various therapeutic regimens.

The PET scan images obtained in steps (b) and (d) of the methods described above may be combined with, preceded by, and/or followed by anatomical imaging selected from computed tomography (CT) imaging, computerized axial tomography (CAT) imaging, or MRI. For combined imaging, the images can be acquired using a dedicated PET-CT, PET-MRI, or separate PET and CT/MRI scanning devices. If separate PET and CT/MRI imaging devices are used, image analysis techniques can be employed to spatially register the PET images with the anatomical images.

In at least one embodiment, the image acquisition steps (b) and (d) involve obtaining a combined PET scan image and MRI scan image. The PET-MRI images can be obtained using a dedicated PET-MRI scanning device. Such scanning devices are available from Siemens (Biograph mMR) and GE (SIGNA PET/MR). Since MRI does not use any ionizing radiation, its use is generally favoured in preference to CT. An advantage of PET-MRI acquisition is that the patient and medical staff generally only need to be present for a single scan resulting in a more time and cost efficient process.

In at least one embodiment, the image acquisition steps (b) and (d) involve obtaining a combined PET scan image and CT scan image. The PET-CT images can be obtained using a dedicated PET- CT scanning device. An advantage of PET-CT acquisition is that the patient and medical staff generally only need to be present for a single scan resulting in a more time and cost efficient process.

The methods described herein can be used for intra-organ mapping of lesion location, for example, the spatial distribution of brain lesion tissue within the brain can be determined for aiding in biopsy or treatment planning of the brain lesion.

The methods described herein may be performed prior to surgery to plan biopsy or surgical field, prior to radiotherapy to plan radiation field, after surgery, radiation or systemic treatment to assess response or plan subsequent treatment, to differentiate between treatment-related effects (including radiation necrosis/pseudo-progression) and recurrence of metastasis or as prognostic aid.

The methods described herein may be suitable for detecting metastasis formation derived from brain lesions. [¹⁸F]-FACBC can be used in the detection and localisation of a wide variety of metastatic cancers that may be present in the brain.

The methods described herein may be suitable for detecting recurrence of metastasis within brain lesions. [¹⁸F]-FACBC is particularly useful for imaging brain lesions.

In at least one embodiment, the methods herein are used to diagnose recurrent brain metastasis. For example, any of the methods above may be used for a subject previously diagnosed with brain metastasis.

The methods of the present disclosure have use in humans and some methods may have use in non-human animals (for example, dogs and cats). That is, the subject or patient may be a human or a non-human animal.

Aspects of the present disclosure provide a kit for imaging, diagnosing or monitoring metastatic cancer, comprising: a) [¹⁸F]-FACBC tracer; and b) administration instructions in accordance with any of the aspects of the present disclosure. For example, the administration instructions may include instructions for the patient to consume no food or calorie-containing drink during a given period of time prior to the administration of [¹⁸F]-FACBC. Additionally or alternatively, the administration instructions may include instructions for a medical professional to inject the [¹⁸F]- FACBC into the subject, e.g., as a bolus intravenous injection, optionally followed by a saline flush, such as a saline flush of about 10 mL or less. The instructions may include dosing information. Further, the administration instructions can include instructions for the medical professional to begin acquisition of a PET scan image 8 to 12 minutes after the end of the injection, such as about 10 minutes after the end of the injection.

Aspects of the present disclosure include the following numbered paragraphs. 1. A method of using anti-l-amino-3-¹⁸F-fluorocyclobutane-l-carboxylic acid ([¹⁸F]-FACBC), comprising the steps of:

(a) administering a detectable amount of [¹⁸F]-FACBC to a subject;

(c) analysing the one or more PET scan images by: (i) comparing [¹⁸F]-FACBC uptake in a potential lesion of the head region of the subject against [¹⁸F]-FACBC uptake in the venous sinus of the head region; or, (ii) comparing a standardized uptake value (SUV) of [¹⁸F]-FACBC uptake in a potential lesion against a reference threshold standardized uptake value (SUV)threshoid; or (iii) a combination of steps (i) and (ii); and

2. The method of paragraph 1, wherein the brain lesion is a cancer lesion.

3. The method of paragraph 2, wherein the cancer lesion is a metastatic cancer lesion.

4. The method of paragraph 1, wherein step (c)(i) comparing [¹⁸F]-FACBC uptake in the potential lesion against [¹⁸F]-FACBC against uptake in the venous sinus comprises making a visual comparison of the PET scan image of said potential lesion against said venous sinus.

5. The method of paragraph 4, wherein step (d) includes identifying the potential lesion as a brain lesion, especially a metastatic cancer lesion or recurrence thereof, when the PET scan image of the potential lesion exhibits greater intensity compared with the PET scan image of the venous sinus.

6. The method of paragraph 4, wherein step (d) includes identifying the potential lesion as not a brain lesion, when the PET scan image of the potential lesion exhibits lower intensity compared with the PET scan image of the venous sinus. 7. The method of paragraph 1 including step (c)(i) and wherein step (d) includes identifying that the potential lesion is a brain lesion, especially a metastatic cancer lesion or recurrence thereof, when the amount of [¹⁸F]-FACBC uptake in the potential lesion is greater than the amount of [¹⁸F] - FACBC uptake in the venous sinus.

8. The method of paragraph 1, wherein step (c)(ii) comprises comparing the maximum standardized uptake value (SUV)_max of [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold maximum standardized uptake value (SUV)threshoid-max, wherein said reference threshold maximum standardized uptake value (SUV)threshoid-max is a value of 4.0 to 4.1.

9. The method of paragraph 8, wherein said reference threshold maximum standardized uptake value (SUV)threshoid-max is a value in the range of 4.0 to 5.0.

10. The method of paragraph 8 or 9, wherein step (d) includes identifying that the potential lesion is a brain lesion, especially a metastatic cancer lesion or recurrence thereof, when the maximum standardized uptake value (SUV)_ma_Xof [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to the reference threshold maximum standardized uptake value (SUV)threshoid-max.

11. The method of paragraph 1, wherein step (c)(ii) comprises comparing the peak standardized uptake value (SUV)_peak of [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold peak standardized uptake value (SUV)threshoid-peak, wherein said reference threshold peak standardized uptake value (SUV)threshoid-peakis a value of 2.0 to 2.1.

12. The method of paragraph 11, wherein said reference threshold peak standardized uptake value (SUV)threshoid-peak is a value in the range of 3.0 to 4.0.

13. The method of paragraph 11 or 12, wherein step (d) includes identifying that the potential lesion is a brain lesion, especially a metastatic cancer lesion or recurrence thereof, when the peak standardized uptake value (SUV)_peakof [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to the reference threshold peak standardized uptake value (SUV)threshoid-peak. 14. The method of paragraph 1, wherein step (c) comprises a combination of step (c)(i) and step (c)(ii).

15. The method of paragraph 14, wherein step (c)(ii) comprises: (c)(ii)(a) comparing the maximum standardized uptake value (SUV)_max of [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold maximum standardized uptake value (SUV)threshoid-max, wherein said reference threshold maximum standardized uptake value (SUV)threshoid-maxis a value of 4.0 to 4.1; or (c)(ii)(b) comparing the peak standardized uptake value (SUV)_peak of [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold peak standardized uptake value (SUV)threshoid-peak, wherein said reference threshold peak standardized uptake value (SUV)threshoid-peak is a value of 2.0 to 2.1; or, a combination of (c)(ii)(a) and (c)(ii)(b).

16. The method of paragraph 14 or 15, wherein step (d) includes identifying that the potential lesion is a brain lesion, especially a metastatic cancer lesion or recurrence thereof, when (i) the amount of [¹⁸F]-FACBC uptake in the potential lesion is greater than the amount of [¹⁸F]-FACBC uptake in the venous sinus of the head region and also (ii) the standardized uptake value (SUV) of the [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to the reference threshold standardized uptake value (SUV)threshoid.

17. The method of paragraph 1, wherein step (d) includes identifying that the potential lesion is not a brain lesion when the amount of [¹⁸F]-FACBC uptake in the potential lesion is less than the amount of [¹⁸F]-FACBC uptake in the venous sinus.

18. The method of paragraph 8, wherein step (d) includes identifying that the potential lesion is not a brain lesion when the maximum standardized uptake value (SUV)_ma_Xof [¹⁸F]-FACBC uptake in the potential lesion is less than the reference threshold maximum standardized uptake value (SUV)threshold -max*

19. The method of paragraph 1, wherein acquiring the PET scan image starts 8 to 12 minutes, preferably 10 minutes, after the administration of the [¹⁸F]-FACBC. 20. The method of paragraph 1, wherein the [¹⁸F]-FACBC is administered as an intravenous bolus injection.

21. The method of paragraph 1, wherein the detectable amount of [¹⁸F]-FACBC administered to the subject is 185 ± 20% MBq.

22. The method of paragraph 1, wherein step (a) further comprises the subject following instructions to consume no food or calorie-containing drink during a period of time prior to the administration of the [¹⁸F]-FACBC, preferably for a period of at least 4 hours prior to the administration of the [¹⁸F]-FACBC.

23. The method of paragraph 1, wherein step (b) comprises acquiring a first PET scan image and at least one subsequent second PET scan image, and wherein step (c) comprises comparing intensities of [¹⁸F]-FACBC uptake in the first PET scan image and the at least one subsequent second PET scan image to determine whether the intensity of [¹⁸F]-FACBC uptake in the at least one subsequent second PET scan image has increased, remained constant, or decreased relative to the intensity of [¹⁸F]-FACBC uptake of the first PET scan image.

Although the present disclosure has been described above with reference to exemplary embodiments, it is not intended to be limited to the specific form set forth herein. Rather, the invention is limited only by the accompanying claims and, other embodiments than those above are equally possible within the scope of these appended claims.

Claims

1. A method of using anti-l-amino-3-¹⁸F-fluorocyclobutane-l-carboxylic acid ([¹⁸F]- FACBC), comprising the steps of:

(a) administering a detectable amount of [¹⁸F]-FACBC to a subject;

(b) acquiring one or more positron emission tomography (PET) scan images of a head region of the subject, the head region including a venous sinus;

(c) analysing the one or more PET scan images by:

(i) comparing [¹⁸F]-FACBC uptake in a potential lesion of the head region of the subject against [¹⁸F]-FACBC uptake in the venous sinus of the head region; or

(ii) comparing a standardized uptake value (SUV) of [¹⁸F]-FACBC uptake in a potential lesion against a reference threshold standardized uptake value (SUV)threshoid; or

(iii) a combination of steps (i) and (ii); and

2. Anti-l-amino-3-¹⁸F-fluorocyclobutane-l-carboxylic acid ([¹⁸F]-FACBC) for use in determining whether a potential lesion of the head region of a subject is a brain lesion, the use comprising the steps of:

(a) administering a detectable amount of [¹⁸F]-FACBC to a subject;

(c) analysing the one or more PET scan images by:

(i) comparing [¹⁸F]-FACBC uptake in a potential lesion of the head region of the subject against [¹⁸F]-FACBC uptake in the venous sinus of the head region;

(ii) comparing a standardized uptake value (SUV) of the [¹⁸F]-FACBC uptake in a potential lesion against a reference threshold standardized uptake value (SUV)threshoid; or

(iii) a combination of steps (i) and (ii); and

(d) determining whether the potential lesion is a brain lesion based on the analysis of step (c)

39

3. The method or compound of any preceding claim, wherein the brain lesion is a cancer lesion.

4. The method or compound of claim 3, wherein the cancer lesion is a metastatic cancer lesion.

5. The method or compound of any preceding claim, wherein step (c)(i) comparing [¹⁸F]- FACBC uptake in the potential lesion against [¹⁸F]-FACBC against uptake in the venous sinus comprises making a visual comparison of the PET scan image of the potential lesion against the venous sinus.

6. The method or compound of claim 5, wherein step (d) includes: identifying the potential lesion as a metastatic cancer lesion or recurrence thereof when the PET scan image of the potential lesion exhibits greater intensity compared with the PET scan image of the venous sinus; or identifying the potential lesion as not a brain lesion, when the PET scan image of the potential lesion exhibits lower intensity compared with the PET scan image of the venous sinus.

7. The method or compound of any one of claims 1 to 5 including step (c)(i) and wherein step (d) includes identifying that the potential lesion is a metastatic cancer lesion or recurrence thereof, when the amount of [¹⁸F]-FACBC uptake in the potential lesion is greater than the amount of [¹⁸F] - FACBC uptake in the venous sinus.

8. The method or compound of any one of claims 1 to 4, wherein step (c)(ii) comprises comparing the maximum standardized uptake value (SUV)_max of [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold maximum standardized uptake value (SUV) thresholdmax, wherein the reference threshold maximum standardized uptake value (SUV)threshoid-max is a value of 4.0 to 4.1.

9. The method or compound of claim 8, wherein the reference threshold maximum standardized uptake value (SUV)threshoid-max is a value in the range of 4.0 to 5.0.

40

10. The method or compound as claimed in claim 8 or 9, wherein step (d) includes identifying that the potential lesion is a metastatic cancer lesion or recurrence thereof, when the maximum standardized uptake value (SUV)_ma_Xof [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to the reference threshold maximum standardized uptake value (SUV)threshoid-max.

11. The method or compound of any one of claims 1 to 4, wherein step (c)(ii) comprises comparing the peak standardized uptake value (SUV)_peak of [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold peak standardized uptake value (SUV)threshoid-peak, wherein the reference threshold peak standardized uptake value (SUV)threshoid-peakis a value of 2.0 to 2.1.

12. The method or compound of claim 11, wherein the reference threshold peak standardized uptake value (SUV)threshoid-peakis a value in the range of 3.0 to 4.0.

13. The method or compound of claim 11 or 12, wherein step (d) includes identifying that the potential lesion is a metastatic cancer lesion or recurrence thereof, when the peak standardized uptake value (SUV)_peak of [¹⁸F]-FACBC uptake in the potential lesion is greater than or equal to the reference threshold peak standardized uptake value (SUV)threshoid-peak.

14. The method or compound of any one of the preceding claims, wherein step (c) comprises a combination of step (c)(i) and step (c)(ii).

15. The method or compound of claim 14, wherein step (c)(ii) comprises:

(c)(ii)(a) comparing the maximum standardized uptake value (SUV)_max of [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold maximum standardized uptake value (SUV)threshoid-max, wherein the reference threshold maximum standardized uptake value (SUV)threshoid-max is a value of 4.0 to 4.1; or

(c)(ii)(b) comparing the peak standardized uptake value (SUV)_peak of [¹⁸F]-FACBC uptake in the potential lesion against a reference threshold peak standardized uptake value (SUV)threshoid- peak, wherein the reference threshold peak standardized uptake value (SUV)threshoid-peakis a value of 2.0 to 2.1; or

41 a combination of (c)(ii)(a) and (c)(ii)(b).

16. The method or compound of claim 15 or 16, wherein step (d) includes identifying that the potential lesion is a metastatic cancer lesion or recurrence thereof, when (i) the amount of [¹⁸F] - FACBC uptake in the potential lesion is greater than the amount of [¹⁸F]-FACBC uptake in the venous sinus of the head region and also (ii) the standardized uptake value (SUV) of the [¹⁸F]- FACBC uptake in the potential lesion is greater than or equal to the reference threshold standardized uptake value (SUV)threshoid.

17. The method or compound of any one of the preceding claims, wherein step (d) includes identifying that the potential lesion is not a brain lesion when the amount of [¹⁸F]-FACBC uptake in the potential lesion is less than the amount of [¹⁸F]-FACBC uptake in the venous sinus.

18. The method or compound of any one of claims 8 to 10, wherein step (d) includes identifying that the potential lesion is not a brain lesion when the maximum standardized uptake value (SUV)max of [¹⁸F]-FACBC uptake in the potential lesion is less than the reference threshold maximum standardized uptake value (SUV)threshoid-max.

19. The method or compound of any one of the preceding claims, wherein acquiring the PET scan image starts 8 to 12 minutes after the administration of the [¹⁸F]-FACBC; or wherein the subject has followed instructions to consume no food or calorie-containing drink for a period of at least 4 hours prior to the administration of the [¹⁸F]-FACBC.

20. The method or compound of any one of the preceding claims, wherein the [¹⁸F]-FACBC is administered as an intravenous bolus injection, or wherein the detectable amount of [¹⁸F]-FACBC administered to the subject is 185 ± 20% MBq.

21. The method or compound of any one of the preceding claims, wherein step (b) comprises acquiring a first PET scan image and at least one subsequent second PET scan image, and wherein step (c) comprises comparing intensities of [¹⁸F]-FACBC uptake in the first PET scan image and the at least one subsequent second PET scan image to determine whether the intensity of [¹⁸F]- FACBC uptake in the at least one subsequent second PET scan image has increased, remained constant, or decreased relative to the intensity of [¹⁸F]-FACBC uptake of the first PET scan image.