PET-CT imaging method, contrast agent and pharmaceutical composition for use in the imaging method

Abstract

The present invention describes a method for distinguishing tumor tissue from brown adipose tissue in PET-CT scans. In particular, the present invention relates to a method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue by PET-CT imaging in human cancer patients.

Description

[Technical Field]

[0001] The present invention describes a method for distinguishing tumor tissue from brown adipose tissue in PET-CT scans using medical imaging agents. In particular, the present invention relates to a method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue in human cancer patients by PET-CT imaging. A prognostic method for cancer assessment by assessing the amount of activated brown and / or beige tissue in human cancer patients by PET-CT imaging is also described. [Background technology]

[0002] Positron emission tomography (PET) is an imaging technique that uses radioactive materials to visualize and measure metabolic processes in the body. PET is primarily used in medical imaging to detect or measure changes in physiological activities such as metabolism, blood flow, local chemical composition, and absorption.

[0003] PET scans require the administration of a radioactive tracer to the patient before the scan is performed. The most commonly used PET tracers are: 18 FDG (2-[fluorine-18]fluoro-2-deoxy-D-glucose) is a tracer used to identify increased glycolytic activity in tissues, especially malignant cells, where glucose is preferentially concentrated due to an increase in membrane glucose transporters and some of the key enzymes responsible for glucose phosphorylation, such as hexokinase. 18 Like glucose, FDG is transported into tumor cells using glucose transporter proteins known as GLUT transporters, and is then phosphorylated by hexokinase. 18 It becomes FDG 6-phosphate. 18 FDG 6-phosphate is not metabolized efficiently any more and therefore accumulates within the cell. 18 The process of "metabolic capture" of FDG is 18 FDG PET constitutes the basis for imaging the in vivo distribution of tracers.18 The concentration of the FDG tracer corresponds to local glucose uptake and is therefore indicative of tissue metabolic activity. 18 FDG is used to detect the potential spread of cancer to other parts of the body (cancer metastasis). 18 FDG PET scans are the most common in standard medical care (accounting for 90% of current PET scans). They can image the entire body in a single session, increasing the chance of finding unexpected disease sites.

[0004] Computed tomography (CT), on the other hand, is a medical imaging procedure that uses a computerized combination of several X-ray measurements taken from different angles to produce cross-sectional (tomographic) X-ray images of specific areas of the scanned subject.

[0005] PET-CT combines a PET scanner and a CT scanner to acquire images from both devices in the same (single) scanning session and combine these images into a single image, thus allowing precise anatomical alignment of functional imaging acquired by PET.

[0006] 18 FDG PET-CT scans are used to diagnose and / or stage and / or restage, and / or assess disease dissemination (metastasis) and / or therapy response in the following malignancies: lung, colorectal, breast, gynecological, head and neck, esophageal, gastric, biliary tract, follicular and medullary thyroid, and pancreatic cancer, melanoma, lymphoma, multiple myeloma, sarcoma, primary brain tumors, and other tumors. 1 .

[0007] Brown adipose tissue (BAT) is responsible for cold- and food-induced nonshivering thermogenesis. BAT also mediates increased energy expenditure in patients with cancer and chronic diseases. 18FDG can be taken up by brown adipose tissue in the neck (cervical), shoulder (supraclavicular), paravertebral region, mediastinum, perirenal and perigastric regions. Uptake in other non-classical areas has also been observed.

[0008] Beige adipose tissue is another type of thermogenic adipose tissue that arises in white adipose depots in response to physiopathological stimuli and has similar functions to brown adipose tissue.

[0009] Although highly sensitive in identifying the site of malignancy, 18 FDG PET is not very specific for cancer tissue. False-positive results can be observed in benign disease, with a reported false-positive rate of 13% and a false-negative rate of 9%. 2 If not properly recognized, these false positive areas of metabolic activity have the potential for significant morbidity and mortality. 3 . 18 Brown adipose tissue uptake of FDG has been reported to be observed in 5-10% of patients. 4,5 This is especially common in women and children during cold weather months. 6 in brown adipose tissue (BAT) in children 18 Frequent FDG uptake has been described. 18 FDG uptake is 18 It has been reported in up to 50% of children undergoing FDG PET scans. Hong et al. 6 in brown lipids 18 They also described parameters that influence FDG uptake (e.g., age, gender, environmental temperature, etc.). 18 Current methods to reduce FDG uptake: pharmacological approaches (opiates and benzodiazepines), diet (high-fat, low-carbohydrate meal the night before the scanning procedure), and 18 The heating before and after injection of FDG is described.

[0010] Steinberg et al. 7However, PET-CT scans of some patients showed poor BAT 18 This paper describes the uptake of FDG and factors that influence this uptake in BAT. 18 FDG uptake present 18 The rate of FDG PET-CT scans can reach 17% in patients with lymphoma and 17-80% in patients with breast cancer. There is tracer uptake in brown adipose tissue. 18 In 15% of FDG PET-CT scans, nuclear medicine physicians are unable to evaluate the scan due to uncertainty. 7 According to the study, it is unclear why BAT is activated in some patients and not in others, or what is involved in BAT activation. 18 It is unclear why FDG uptake varies between patients. 18 They also explain that FDG uptake is a confounding factor that can lead to erroneous conclusions (false positive or false negative). 18 They describe patient characteristics (gender, age, BMI) that increase the likelihood of having FDG uptake. Finally, they cite outdoor temperature and the duration of the scanning procedure as influencing factors.

[0011] Cohade et al. 8 However, this is a problem that needs to be solved (in BAT) 18 The authors describe the impact of FDG uptake and PET-CT on the progression of glaucoma (including glaucoma), as well as factors such as age, sex, and BMI.

[0012] in hypermetabolic brown adipose tissue 18 FDG uptake is 18 It is well recognized as a potential source of false positives in FDG PET-CT imaging. 3,9 In fact, Long et al. 9 teeth, 18describe the risk of false positives and false negatives in FDG PET-CT scans. They strongly advise physicians to use CT scans to help reach a conclusion (tumor or BAT uptake). They also suggest that BAT activation and therefore BAT uptake may be involved. 18 Several pharmacological approaches have been proposed as solutions to prevent FDG deposition (administration of propranolol or keeping the patient warm).

[0013] Wang et al. 10 However, one of the problems that needs to be solved is the 18 This paper describes the differentiation of FDG uptake in BAT from that in tumor tissue. The oral CT contrast agent described in this paper outlines only the gastrointestinal tract, and in this case there is no systemic uptake of the oral contrast agent. 18 It is also noted that benzodiazepines (diazepam) can be used to block FDG uptake.

[0014] in brown adipose tissue using pharmacological methods 18 Although FDG uptake can be reduced, patients are subsequently at higher risk of adverse reactions. Furthermore, pre-scan pharmacological treatment is not recommended and should be used with caution in the pediatric population. 18 Reduction of FDG uptake is usually achieved by keeping the patient warm and during the uptake phase ( 18 This is only attempted by providing the patient with a blanket between the FDG injection and the PET scan. The current method for distinguishing metastases from brown adipose tissue on a PET scan is by comparing the results of the PET scan with detailed and time-consuming analysis of axial slices of the CT scan by a nuclear medicine physician and a radiologist, respectively. 18 If areas of FDG uptake correspond to lipid attenuation on the CT scan, the tracer uptake is due to brown adipose tissue activation.

[0015] WO2008 / 153928A2 11(KOLODNY GERALD [US], WILLIAMS GETHIN [US]) 18 We describe a method for reducing FDG uptake in BAT (and myocardium): 18 It involves adherence to a high-fat, no-carbohydrate, low-protein diet for several hours before the FDG PET-CT scan.

[0016] WO2019 / 030024A1 12 (UNIV GENEVE [CH]) describes an iodinated CT contrast agent made with a fatty acid derivative for the noninvasive visualization and quantification of brown and beige adipose tissue. One notable feature of this contrast agent is that it is given via the oral route to provide contrast to brown adipose tissue. The brown adipose tissue is then detected by CT scanning. This CT contrast agent is used in the context of a CT scan to detect only brown adipose tissue.

[0017] 18 Poorer outcomes are observed in cancer patients with high brown adipose tissue activity and / or volume and / or surface area, as characterized by FDG uptake 13 In these patients, the more metabolically active brown adipose tissue ( 18 (characterized by FDG uptake) was associated with a more active neoplastic state. In particular, Huang et al. 13 described that neoplastic status is a significant determinant of BAT activity in patients living in the tropics, where the effect of outdoor temperature on BAT activation is minimal. However, the authors found that 30 of 1740 patients 18 FDG PET-CT scans were performed (37 of 1903) 18 The conclusion was based on the fact that FDG PET-CT scans were positive for BAT. BAT activity was 18 Quantified by FDG PET-CT scan. Of 1171 patients with a history of cancer, only 21 (1.8%) had BAT. 18These results suggest that FDG deposition is 18 It can be concluded that FDG PET-CT scans clearly lack the sensitivity to detect BAT. 18 The estimated sensitivity of FDG PET-CT scans for BAT currently ranges between 1.8 and 10%.

[0018] Abnormal BAT volume and / or surface area and / or activity have been associated with an increased likelihood of tumor recurrence and / or tumor-related mortality. 14 This may be related not only to tumor progression and / or severity (inflammatory and tumor factors promoting brown adipose tissue activation and white adipose tissue browning), but also to the occurrence of bodily wasting—cachexia. Indeed, Chu et al. 14 is BAT positive 18 FDG PET scans have been associated with cancer progression and cancer-related mortality. However, the results presented are limited to BAT-positive 18 Based on 132 patients who had FDG PET scans. How many cancer patients were BAT negative? 18 It is unclear whether the patients had FDG PET scans, but the authors themselves did not have any prior experience with BAT to assess its presence and / or activity. 18 point out the lack of sensitivity of FDG PET scans.

[0019] Bos et al. 15 is BAT positive 18 We found that FDG PET scans were significantly more relevant in patients with active cancer than in those without. However, again, the sample size was very small (142 patients out of 21,262, or 0.66%), and we were unable to detect and quantify BAT under standard PET scan conditions. 18 The lack of sensitivity of FDG PET scans was noted.

[0020] Abnormal BAT volume and / or surface area and / or activity may be increased or decreased compared to the BAT volume and / or surface area in healthy subjects. Currently, tumor staging and cancer prognosis are usually based on the TNM staging system, which is a classification system for the anatomical extent of tumors.

[0021] TNM is a notation system for describing the stage of cancer originating from solid tumors, using the following alphanumeric codes: - T describes the size of the primary tumor and whether it has invaded nearby tissues; - N describes the nearby (regional) lymph nodes involved, - M describes distant metastasis.

[0022] This staging system can give some indication of the outcome of the cancer at the time of diagnosis (the higher the grade of the cancer, the worse its prognosis), but it does not give any indication of the aggressiveness of the cancer. Summary of the Invention [Problem to be solved by the invention]

[0023] Unfortunately, in some anatomical areas 18 There are currently no validated methods to confirm that FDG uptake is due to metabolically active brown adipose tissue and not due to tumor or metastasis. In some cases, nuclear medicine physicians and radiologists cannot reach a meaningful conclusion. 18 FDG PET-CT scans must be repeated, resulting in additional exposure of the patient to radiation, increased time spent in hospital settings for the patient, and additional costs for the healthcare system and / or the patient. [Means for solving the problem]

[0024] The present invention relates to means and methods for overcoming the deficiencies of the prior art discussed above. In particular, the present invention relates to PET-CT contrast agents and 18Various methods, imaging agents for use, and pharmaceutical compositions for use are provided that increase the accuracy of determinations based on imaging methods involving the use of PET tracers such as FDG. These methods of the invention, imaging agents for use in accordance with the invention, and pharmaceutical compositions for use in accordance with the invention are specified in the appended claims and in the numbered paragraphs of specific embodiments described below.

[0025] Further information about the means and methods of the present invention is set forth in the detailed description below. More particularly, the present invention relates to, inter alia: 18 FDG PET-CT scan for metastases and / or tumors 18 A method for distinguishing FDG uptake from brown adipose tissue is provided. 18 This method comprises administering to the patient a PET-CT contrast agent that specifically accumulates in brown adipose tissue prior to an FDG PET-CT scan. The PET-CT contrast agent is preferably administered to the patient via the oral route, but may also be administered via other routes (intravenous, intrathecal, intralymphatic, intraarterial, intraperitoneal, subcutaneous). In some embodiments, the PET tracer ( 18 Colocalized signals from FDG and PET-CT contrast agents in brown adipose tissue 18 This may be due to FDG uptake.

[0026] Wang et al. 10 In contrast, the present invention is 18 It is not about reducing FDG uptake, 18 FDG PET-CT scan in tumor tissue 18 We aim to use BAT-specific medical imaging agents to distinguish FDG uptake in BAT from that in BAT.

[0027] One object of the present invention is to provide a method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue by PET-CT imaging in human cancer patients. The method comprises: a) administering to said human cancer patient a compound of general formula I:

[0028] [ka] (wherein n=14 to 16, R1 is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is selected from H, unsaturated or saturated, linear or branched alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl, aryl, aryloxy, arylcarbonyl, arylcarbonylalkyl, heteroaryl, non-aromatic heterocycle, or alkylcarbonyloxyalkyl, which may be substituted with one or more, preferably 1 to 5, more preferably 1, 2, 3, or 4, substituents, each independently selected from aryl, heteroaryl, halogen, hydroxy, alkyl, alkoxy, aryloxy, and non-aromatic heterocycle. Each of these halogen substituents may be independently selected from F, Cl, Br, and I. When multiple iodine atoms are present, the same proviso as defined herein for the R1 group applies, i.e., there may not be two iodine atoms in either geminal or vicinal positions. It is also possible to rely on preferred R2 groups as described below. Yet another option is to use a compound of formula A, B or C as described below: administering a PET-CT contrast agent comprising an iodinated fatty acid and / or an ester and / or a salt and / or a mixture thereof according to b) at least 3 hours after administration of the PET-CT contrast agent of step a), 18 administering an FDG PET tracer; c) for the human cancer patient 18 The process of performing FDG PET-CT scan Includes:

[0029] As noted above, in some embodiments, step c) 18 FDG PET-CT scan 18 It is used for colocalization of the positive contrast enhancement of FDG and the PET-CT contrast agent.

[0030] Another object of the present invention is to provide a method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue by PET-CT imaging in human cancer patients. The method comprises: a) administering to said human cancer patient a compound of general formula I:

[0031] [ka] (wherein n=14 to 16, R1 is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is selected from H, unsaturated or saturated, linear or branched alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl, aryl, aryloxy, arylcarbonyl, arylcarbonylalkyl, heteroaryl, non-aromatic heterocycle, or alkylcarbonyloxyalkyl, which may be substituted with one or more, preferably 1 to 5, more preferably 1, 2, 3, or 4, substituents, each independently selected from aryl, heteroaryl, halogen, hydroxy, alkyl, alkoxy, aryloxy, and non-aromatic heterocycle. Each of these halogen substituents may be independently selected from F, Cl, Br, and I. When multiple iodine atoms are present, the same proviso as defined herein for the R1 group applies, i.e., there cannot be two iodine atoms in either geminal or vicinal positions. It is also possible to rely on the preferred R2 groups as described below. Yet another option is to use a compound of formula A, B, or C as described below. administering a PET-CT contrast agent comprising an iodinated fatty acid and / or an ester and / or a salt and / or a mixture thereof according to b) administering a PET tracer at least 3 hours after administration of the PET-CT imaging agent of step a); c) performing a PET-CT scan on the human cancer patient; Includes:

[0032] Yet another object of the present invention is a method for identifying metabolic diseases in a human subject by PET-CT imaging of brown and / or beige adipose tissue in said human subject, comprising: a) administering to the human subject a compound of general formula I:

[0033] [ka] (wherein n=14 to 16, R1 is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is selected from H, unsaturated or saturated, linear or branched alkyl, alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl, aryl, aryloxy, arylcarbonyl, arylcarbonylalkyl, heteroaryl, non-aromatic heterocycle, or alkylcarbonyloxyalkyl, which may be substituted with one or more, preferably 1 to 5, more preferably 1, 2, 3, or 4, substituents, each independently selected from aryl, heteroaryl, halogen, hydroxy, alkyl, alkoxy, aryloxy, and non-aromatic heterocycle. Each of these halogen substituents is independently selected from F, Cl, Br, and I. When multiple iodine atoms are present, the same proviso as defined herein for the R1 group applies, i.e., there cannot be two iodine atoms in either geminal or vicinal positions. It is also possible to rely on the preferred R2 groups as described below. Yet another option is to use a compound of formula A, B, or C as described below. administering a PET-CT contrast agent comprising an iodinated fatty acid and / or an ester and / or a salt and / or a mixture thereof according to b) at least 3 hours after administration of the PET-CT contrast agent of step a), 18 administering an FDG PET tracer; c) to said human subject 18 The process of performing FDG PET-CT scan The object of the present invention is to provide a method comprising:

[0034] In some embodiments of this method, step c) 18 FDG PET-CT scan 18 It is used for colocalization of the positive contrast enhancement of FDG and the PET-CT contrast agent.

[0035] In a variation of the above method, 18It is possible to use PET tracers other than FDG. The PET-CT scan of step c) would of course have to be adapted to the alternative PET tracer, but otherwise the method can be carried out as outlined above.

[0036] Those skilled in the art will appreciate that brown adipose tissue volume and / or surface area and / or activity can be low, medium, or high as assessed from PET-CT scans. For example, a low BAT volume can be 100 mL or less, a medium BAT volume can be between 100-200 mL, and a high BAT volume can be greater than 200 mL. 16 .

[0037] One skilled in the art can then assess tumor progression and cancer prognosis with PET-CT scans.

[0038] The uptake of PET-CT contrast agents by brown adipose tissue, as observed on PET-CT scans, correlates with the prognosis of cancer patients, depending on the cancer type. For most cancers, higher uptake than healthy people indicates a poor prognosis and warrants additional medical attention for these patients. For other malignancies, particularly those affected by hormones (such as some breast cancers), higher uptake indicates a better cancer outcome.

[0039] Both objectives of the present invention (detection of malignant tissue and assessment of cancer prognosis) can be performed simultaneously by a single PET-CT scan.

[0040] Other objects and advantages of the present invention will become apparent to those skilled in the art from a review of the ensuing detailed description, which proceeds with reference to the following illustrative drawings and the appended claims. [Brief explanation of the drawings]

[0041] [Figure 1]

[0023] Figures 1A-1B illustrate a description of one of the problems solved by the present invention, namely, 18FDG uptake in brown adipose tissue, which can lead to misinterpretation. A: 18FDG PET scan of a 56-year-old woman with non-small cell lung cancer. Black arrow: active lung cancer. White arrow: brown adipose tissue. From Bos et al., 2019. B: 18FDG PET scan of a 13-year-old boy with widespread 18FDG uptake by BAT in the neck and supraclavicular-axillary, paravertebral-intercostal, and mediastinal regions. Arrows: rare, continuous, curvilinear uptake around the lateral border of the kidney. From Hong et al., 2016. C: 18FDG PET scan (arrow) of a 15-year-old girl with asymmetric 18FDG uptake in BAT in the upper neck. [Figure 2] a: Axial PET-CT scans of a mouse with metastatic melanoma with and without PET-CT contrast. Top: 18FDG PET-CT scan without PET-CT contrast. Bottom: 18FDG PET-CT scan with PET-CT contrast. Left: 18FDG PET scan. Black arrows point to 18FDG-positive areas (metastases and / or BAT). Right: 18FDG PET-CT scan. 18FDG signal in BAT can be excluded as metastasis (white arrow), which is confirmed by necropsy (b: organs in place, arrows = metastases; c: lungs, metastases appear black). [Figure 3] a: Coronal 18FDG PET-CT scans of a mouse with metastatic melanoma with and without PET-CT contrast. Top: 18FDG PET-CT scan without PET-CT contrast. Bottom: 18FDG PET-CT scan with PET-CT contrast. Left: 18FDG PET scan. Black arrows point to 18FDG-positive areas (metastases and / or BAT). Right: 18FDG PET-CT scan. 18FDG signal in BAT is easily excluded as metastasis (white arrow), confirmed by necropsy (b: organs in place, arrows point to metastases; c: lungs, metastases appear black). [Figure 4]Figure 1 shows the positive predictive value of 18FDG PET-CT scans for tumor metastasis without and with a PET-CT contrast agent and the method of the present invention. Based on autopsy (standard of truth), six mice presented with a total of 24 metastases. In the 18FDG PET-CT scans, four mice had positive signals in the BAT, which could be interpreted as false-positive metastases. Without the PET-CT contrast agent and the method of the present invention, the positive predictive value (PPV) of 18FDG PET-CT scans for metastasis was 85%. With the PET-CT contrast agent, the PPV of 18FDG PET-CT scans for metastasis was 100%. Thus, the CT contrast agent of the present invention improves the PPV of 18FDG PET-CT scans for tumor metastasis by only 15%. [Figure 5] 1 shows the sensitivity of 18FDG PET-CT scans of brown adipose tissue without and with a PET-CT contrast agent and the method of the present invention. 18FDG uptake in BAT was present in a total of 9 out of 12 PET-CT scans. However, all mice had BAT (confirmed by autopsy). The sensitivity of 18FDG PET-CT scans of BAT without a PET-CT contrast agent was 75%. With a PET-CT contrast agent, the sensitivity for BAT was 100%. Therefore, the sensitivity of 18FDG PET-CT scans of BAT in mice was improved by 25% using a PET-CT contrast agent and the method of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0042] definition Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of this application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publications by virtue of prior invention. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0043] In case of conflict, the present specification, including definitions, will control.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. As used herein, the following definitions are provided to facilitate the understanding of the present invention.

[0045] Unless otherwise specified or the context dictates otherwise, references to "PET-CT imaging agents" should be understood as references to PET-CT imaging agents as described in the corresponding section below.

[0046] The term "comprise" is generally used in the sense of include, i.e. permitting the presence of one or more features or components. In one specific embodiment, the term "comprise" also encompasses the meaning of the term "consisting of."

[0047] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0048] As used herein, the terms "subject" or "patient" are well-recognized in the art and are used interchangeably herein to refer to mammals, including dogs, cats, rats, mice, monkeys, cows, horses, goats, sheep, pigs, camels, and most preferably humans. In some embodiments, the subject is a subject in need of diagnosis or a subject with a diagnosed disease or disorder. However, in other embodiments, the subject can be a healthy subject. The terms do not denote a particular age or sex. Thus, adult and neonatal subjects, whether male or female, are intended to be encompassed.

[0049] As used herein, a "human cancer patient" is a patient suffering from and / or diagnosed with any type of solid cancer, and preferably a cancer selected from the group consisting of lung, colorectal, breast, gynecological, head and neck, esophageal, gastric, biliary tract, follicular and medullary thyroid, and pancreatic cancer, leukemia, melanoma, lymphoma, multiple myeloma, sarcoma, pheochromacytoma, and primary brain tumors. In some embodiments, the human cancer patient: 18 Patients may or may not have received prior administration of an FDG PET tracer.

[0050] As used herein, and unless otherwise indicated or the context dictates otherwise, the term "area" is intended to characterize a relevant part of the body that appears in an imaging method, the term "surface area" is intended to characterize a quantification, expressed as a numerical value, of the surface area of ​​a relevant part of the body that appears in a 2D projection of the imaging method, and the term "volume" is intended to characterize a quantification, expressed as a numerical value, of the volume of a relevant part of the body that appears in a 3D imaging method. The terms "volume and / or surface area" are intended to refer to volume as defined above in cases where data analysis of the imaging method is performed on 3D data, while they are intended to refer to surface area as defined above in cases where data analysis of the imaging method is performed on 2D data.

[0051] The term "formulation" or "pharmaceutical formulation" encompasses solid formulations such as tablets, enteric-coated tablets, controlled-release tablets, sustained-release tablets, capsules, and self-emulsifying pharmaceutical forms. It also encompasses liquid and semi-solid formulations such as solutions, suspensions, emulsions, topical preparations, suppositories, enemas, and parenteral formulations for injection and infusion.

[0052] The term "biocompatible" is used herein in its commonly used sense, particularly as non-toxic.

[0053] The term "ethiolated oil" refers to an oil of natural origin that is converted by organic synthetic procedures to ethyl esters of iodinated fatty acids used as injectable radiopaque contrast agents, which are used to outline structures in radiological studies. Ethiolated oil is composed of iodine combined with the ethyl esters of fatty acids from poppy seed oil, primarily as ethyl monoiodostearate and ethyl diiodostearate. Although the exact structure is unknown, it is included within the definition of Formula I.

[0054] In chemistry, the term "geminal" as used herein refers to the relationship between two atoms or functional groups that are bonded to the same atom.

[0055] The related term "vicinal" refers to the relationship between two functional groups bonded to adjacent atoms. Currently, it is nearly impossible to synthesize stable iodinated fatty acids and / or esters thereof having iodine atoms bonded to adjacent carbon atoms (i.e., vicinal). Due to steric hindrance, these molecules are unstable and cannot be used for the purposes of the present invention. However, in the future, those skilled in the art may be able to find a technical solution to this problem. Therefore, if stable iodinated fatty acids and / or esters thereof having iodine atoms in vicinal positions are provided, these compounds would also be suitable for solving the technical problem of the present invention.

[0056] As used herein, the term "periodinated" refers to a compound that contains the maximum amount of iodine substituents possible, with the proviso that the compound does not contain any iodine substituents in either the geminal or vicinal positions.

[0057] As used herein, the term "alkyl" includes any long or short chain, straight-chain, branched, or cyclic aliphatic saturated or unsaturated hydrocarbon group, or a group containing a combination of these groups. Unsaturated alkyl groups may be monovalent or polyunsaturated, and include both alkenyl and alkynyl groups. Alkyl, alkenyl, and alkynyl groups may contain up to 40 carbon atoms. However, alkyl, alkenyl, and alkynyl groups containing up to 10, for example, 8, more preferably up to 6, and especially preferably up to 4 carbon atoms are preferred. Of course, the minimum number of carbon atoms is limited by the presence of cycles and unsaturated groups. Thus, saturated alkyl groups can have 1 to 40, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms if they are straight-chained or branched, and 3 to 40, 3 to 10, 3 to 8, 3 to 6, 5 to 6, or 3 to 4 carbon atoms if they are cyclic or contain cyclic alkyl moieties, and unsaturated alkenyl or alkynyl groups can have 2 to 40, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively.

[0058] The term "alkoxyl" or "alkoxy" refers to -O-alkyl. In particular, alkyl groups are alkyl groups as defined above. An example of an alkoxyl is C1-C6 alkoxyl, which represents a straight or branched alkyl chain having from 1 to 6 carbon atoms bonded to an oxygen atom. Exemplary C1-C6 alkoxyl groups include methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, sec-butoxyl, t-butoxyl, pentoxyl, hexoxyl, etc. C1-C6 alkoxyl includes C1-C4 alkoxyl within its definition. Of course, the alkyl group contained in the alkoxy group may have any other meaning specified above, such as, for example, an unsaturated alkenyl or alkynyl group having 2 to 6 carbon atoms.

[0059] In some embodiments of the present invention, the term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, where alkyl and alkoxy are as defined above. An example is a C1-C6 alkyl group bearing a C1-C6 alkoxy group. The number of carbon atoms in the alkoxy group can be selected independently of the number of carbon atoms in the alkyl group.

[0060] In some embodiments of the present invention, the term "hydroxyalkoxyalkyl" refers to an alkoxyalkyl group, as defined above, substituted in the alkoxy portion with a hydroxy group. This group can be illustrated by the following structure: -RO-R'-OH, where R represents an alkyl group as defined above and R' represents the alkyl portion of the alkoxy group -O-R' as defined above.

[0061] In some embodiments of the present invention, the term "polyhydroxyalkyl" refers to an alkyl group as defined above bearing two or more hydroxy groups, for example 2, 3, 4, 5 or 6 hydroxy groups.

[0062] In some embodiments of the present invention, the term "polyalkyleneoxyalkyl" refers to an alkyl group, as defined above, substituted with a polyalkyleneoxy group. Thus, a typical structure of a polyalkyleneoxyalkyl has the following formula: -R-(OR") n -H, where R represents an alkyl group as defined above, R" represents an alkylene group typically having 2, 3 or 4, preferably 2, carbon atoms, and n is selected from the range of 2 to 20, preferably 2 to 10. The number of carbon atoms in the individual alkylene groups need not always be the same, i.e., in the above formula, the number of carbon atoms can be independently selected from 2, 3 or 4 for each alkyleneoxy moiety -OR"

[0063] In some embodiments of the present invention, the term "hydroxypolyalkyleneoxyalkyl" refers to a polyalkyleneoxyalkyl group, as defined above, that is substituted and / or terminated with a hydroxy group. Thus, a typical structure of a hydroxypolyalkyleneoxyalkyl has the following formula: -R-(OR") n -OH, where R represents an alkyl group as defined above, R" represents an alkylene group typically having 2, 3 or 4, preferably 2, carbon atoms, and n is selected from the range of 2 to 20, preferably 2 to 10. The number of carbon atoms in the individual alkylene groups need not always be the same, i.e., in the above formula, the number of carbon atoms can be independently selected from 2, 3 or 4 for each alkyleneoxy moiety -OR"

[0064] In some embodiments of the present invention, the term "alkylcarbonyloxyalkyl" refers to an alkyl group, as defined above, substituted by an alkyl ester group, which typically has the following structure: -RC(=O)-O-R''', where R represents an alkyl group, as defined above, typically having 1 to 6 carbon atoms, and R''' represents an alkyl group, as defined above, typically having 1 to 6 carbon atoms, selected independently from the number of carbon atoms in the R group. According to another variation of the present invention, it is also possible to use groups of this type, but the orientation of the ester group is reversed, i.e., the group is characterized by the following structure: -ROC(=O)-R''', where R represents an alkyl group, as defined above, typically having 1 to 6 carbon atoms, and R''' represents an alkyl group, as defined above, typically having 1 to 6 carbon atoms, selected independently from the number of carbon atoms in the R group. Thus, according to this alternative variation, reference to "alkylcarbonyloxyalkyl" should be understood as a reference to this alternative group in which the orientation of the ester group is reversed. This alternative variant is less preferred. In particular, the main variant mentioned above, represented by the formula -RC(=O)-O-R''', produces superior contrast-enhancing properties and is therefore considered preferred.

[0065] The term "aryl," as used herein, refers to a carbocyclic or heterocyclic, aromatic, 5- to 14-membered monocyclic or polycyclic ring. Exemplary aryls include phenyl, naphthyl, anthryl, phenanthryl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, and benzo[b]thienyl. Examples of quinolyl include benzoyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxylinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl.

[0066] In some embodiments of the present invention, the term "heteroaryl" is used to refer to an aryl group as defined above in which one or more, preferably 1, 2, 3 or 4, more preferably 1 or 2 ring atoms are heteroatoms independently selected from N, O and S. In some embodiments, the heterocyclic aryl groups referred to above are heteroaryl groups as defined herein.

[0067] In some embodiments of the present invention, the term "non-aromatic heterocycle" is used to refer to heterocyclic 5- to 14-membered monocyclic or polycyclic rings having at least one ring atom that cannot participate in a delocalized π-electron system. Typically, they contain 1, 2, 3, or 4 heteroatoms individually selected from N, O, and S. Such non-aromatic heterocycles include fully saturated heterocycles such as tetrahydrofuran and piperidine, as well as partially saturated, partially unsaturated heterocycles such as oxazoline.

[0068] In organic chemistry, a "saturated" compound is a chemical compound with a chain of carbon atoms linked together by single bonds. Alkanes are saturated hydrocarbons. An "unsaturated" compound is a chemical compound that contains a carbon-carbon double or triple bond, such as those found in alkenes or alkynes, respectively. Saturated and unsaturated compounds need not consist solely of a chain of carbon atoms. They can form linear, branched, or cyclic arrangements. They can also have functional groups. In this sense, fatty acids are classified as saturated or unsaturated. The amount of unsaturation in a fatty acid can be determined by finding its iodine value.

[0069] Unsaturated compounds are those that can undergo addition reactions. In carbon chains such as fatty acids, double or triple bonds cause twists in the chain. These twists have macrostructural implications. Unsaturated lipids tend to be liquids rather than solids at room temperature because the twists in the chain prevent the molecules from packing tightly together to form a solid, and these lipids are called oils.

[0070] The terms "polyhydroxy" or "polyhydric" refer to chemical compounds that contain two or more hydroxyl groups per molecule.

[0071] Positron emission tomography-computed tomography (commonly known as PET-CT) is a nuclear medicine technique that combines a positron emission tomography (PET) scanner and an X-ray computed tomography (CT) scanner in a single gantry to acquire images from both devices in the same scanning session. The images are combined into a single overlapping (co-registered) image. Thus, functional images acquired by PET, depicting the spatial distribution of metabolic or biochemical activity in the body, can be precisely aligned or correlated with anatomical images acquired by CT scanning. Two- and three-dimensional image reconstructions can be rendered as a function of common software and control systems.

[0072] As used herein, the term "PET-CT contrast agent" characterizes an agent that enhances the signal or image of a CT scan in a PET-CT measurement. Therefore, a PET-CT contrast agent may also be suitable for performing a CT measurement. As a result, it is typically no different from a CT contrast agent.

[0073] CT does not require the use of contrast agents for anatomical contouring. However, a contrast agent may be administered to the patient prior to the CT scan. This is useful for highlighting structures such as blood vessels that would otherwise be difficult to distinguish from their surroundings. The use of contrast agents can also help obtain functional information about tissues. CT contrast agents are typically administered intravenously. Intra-arterial or intrathecal injections can also be used in some indications. Water-soluble CT contrast agents are used to visualize vascular structures and / or organs. They can also be used to diagnose tumors due to their different uptake and efflux kinetics from surrounding tissues. CT contrast agents can be any molecule intended for vascular imaging, including, but not limited to, iomeprol, ioversol, iopromide, iohexol, iodixanol, diatrizoate meglumine, metrizoate, iothalamate meglumine, iodipamide meglumine, iopamidol, ioxilan, ioxaglate, and ioversol.

[0074] "Overweight and obesity" are defined as abnormal or excessive lipid deposition that presents a risk to health. A body mass index (BMI) greater than 25 is considered overweight, and greater than 30 is obese. Obesity is a medical condition in which excess body fat accumulates to the point that it may have adverse health effects. Obesity is the leading cause of preventable death worldwide, with rates increasing in adults and children.

[0075] "Diabetes" is a chronic metabolic disease characterized by elevated levels of blood glucose (or blood sugar), which over time leads to serious damage to the heart, blood vessels, eyes, kidneys, and nerves. Type 2 diabetes is the most common, and occurs usually in adults when the body becomes resistant to insulin or stops producing enough insulin.

[0076] "Nonalcoholic fatty liver disease" (NAFLD) is a general term that encompasses the entire spectrum of fatty liver disease, from isolated steatosis to NASH.

[0077] NASH stands for "non-alcoholic steatohepatitis." It can be defined as a liver manifestation of metabolic disorder and is the most severe form of non-alcoholic fatty liver disease (NAFLD). NASH is closely associated with the triple epidemic of obesity, prediabetes, and diabetes, but its symptoms are often asymptomatic or non-specific for NASH, making it difficult to diagnose. As a result, NASH patients may remain unaware of their condition until the later stages of the disease. NASH worsens patients' cardiometabolic status and is associated with a higher risk of death caused by cardiovascular events. 18 .

[0078] "Cancer" is a disease characterized by abnormal cell growth that has the potential to invade or spread to other parts of the body. The cancer referred to herein is preferably selected from the group including or consisting of lung, colorectal, breast, gynecological, head and neck, esophageal, gastric, biliary tract, follicular and medullary thyroid, and pancreatic cancer, leukemia, melanoma, lymphoma, multiple myeloma, sarcoma, primary brain tumor, pheochromocytoma, lipoma, or myolipoma.

[0079] In some embodiments, particularly in the context of methods of the present invention involving imaging of patients afflicted with metabolic diseases, the term "healthy" means that a person or patient does not suffer from a metabolic disease, preferably selected from obesity, diabetes, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, particularly in the context of methods of the present invention involving imaging of patients afflicted with cancer, the term "healthy" means that a person or patient does not suffer from cancer.

[0080] "Machine learning" is the science of getting computers to learn and behave like humans, autonomously improving their learning over time by feeding them data and information in the form of observations and real-world interactions. A fundamental goal of machine learning algorithms is to generalize beyond the training examples, i.e., to successfully interpret data that they have never "seen" before.

[0081] "Deep learning," as used herein, refers to a collection of algorithms used in machine learning, which are used to model high-level abstractions in data through the use of model architectures composed of multiple nonlinear transformations. It is part of a broad family of methods used in machine learning based on learned representations of data. Deep learning is a specific approach used to build and train neural networks, which are considered highly promising decision nodes. An algorithm is considered deep if the input data passes through a series of nonlinearities or nonlinear transformations before becoming the output. In contrast, most modern machine learning algorithms are considered "shallow" because the input can only go through a few levels of subroutine calls.

[0082] Deep learning eliminates the manual identification of features in data and instead relies on whatever training process must discover useful patterns in the input examples. This makes neural networks easier and faster to train and can produce better results when applied to measuring bgl.

[0083] Within deep learning, the present invention uses many deep learning methods, including but not limited to: recurrent neural networks and convolutional neural networks.

[0084] A "recurrent neural network" or "RNN" is a class of artificial neural networks in which the connections between nodes form a directed graph along a sequence. This allows them to exhibit temporally dynamic behavior over a time series. They are particularly powerful in use cases where context is critical for predicting outcomes, and they differ from other types of artificial neural networks because they use feedback loops to process sequences of data that convey a final output, which can also be a sequence of data. These feedback loops persist the information.

[0085] In some cases, artificial neural networks process information unidirectionally, from input to output. These "feedforward" neural networks include the convolutional neural networks that underpin image recognition systems. RNNs, on the other hand, are layered and can process information bidirectionally.

[0086] A "convolutional neural network" (CNN) is a type of artificial neural network used primarily in image recognition and processing that is specifically designed to process pixel data. CNNs are powerful image processing networks that use deep learning to perform both generative and descriptive tasks, often used in machine vision, including image and video recognition, along with recommendation systems and natural language processing. These neural networks have their "neurons" arranged in such a way that they cover the entire field of view while avoiding the fragmented image processing problem of traditional neural networks.

[0087] The layers of a CNN consist of an input layer, an output layer, and a hidden layer that includes multiple convolutional, pooling, fully connected, and normalization layers. The removal of limitations and increased efficiency for image processing results in a much more effective and simpler system than training limited to image processing and natural language processing.

[0088] The method of the first embodiment of the present invention In a first embodiment, the present invention provides a method, in particular an imaging method, that allows to distinguish primary tumors and / or metastases from brown and / or beige adipose tissue by PET-CT imaging in human cancer patients. The method comprises: a) administering to said human cancer patient a PET-CT imaging agent as described below; b) at least 3 hours after administration of the PET-CT contrast agent of step a), 18 administering an FDG PET tracer; c) to said human subject 18 The process of performing FDG PET-CT scan Includes:

[0089] Unless otherwise specified, the more specific method of the first embodiment described below includes the above steps a) to c), i.e., the main aspects of the first embodiment.

[0090] In one variation of this embodiment, the present invention provides a method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue by PET-CT imaging in human cancer patients, the method comprising steps a) to c) as specified above. Further specific aspects of the first embodiment are specified below.

[0091] (i) Identification of non-malignant, non-metastatic tissues and identification of malignant or metastatic tissues in cancer patients 18 FDG PET-CT scan 18 It can be used to detect colocalization of positive contrast enhancement of FDG and the PET-CT contrast agent. Such colocalization indicates that the region of interest is neither a malignant tumor nor a metastasis. This information is valuable because it can influence the treating physician / oncologist's decision to proceed with and / or adapt treatment (chemotherapy, radiation therapy, immunotherapy, surgery, and / or other anti-cancer therapy). In some cases, this may allow for avoiding the need for repeat PET-CT medical imaging scans, thus reducing care / treatment time and radiation exposure.

[0092] Identifying metastases becomes easier thanks to the use of the PET-CT imaging agent according to the present invention. Tumor tissue (primary tumor and metastases) can be 18 Visible only through FDG uptake; however, in some cases brown adipose tissue (BAT) is also 18 By depositing FDG, 18 Determining the presence of tumor tissue based solely on FDG uptake carries the risk of false positive results. However, because BAT also accumulates PET-CT contrast agents, the present invention makes it possible to reduce the risk of false positive results. 18 Areas in which both FDG and PET-CT contrast are visible on the PET-CT scan are excluded as metastases.

[0093] Determining the total volume and / or surface area and localization of BAT provides additional valuable information to the treating physician. 18 It is not always visible and / or identifiable as in FDG PET-CT scans. In addition, BAT 18 It cannot be detected using radioactive tracers other than FDG. In the present invention, the contrast of brown and beige adipose tissue is enhanced by the presence of a PET-CT contrast agent (contrast-enhanced positive area).

[0094] Establishment of contrast enhancement of brown and / or beige adipose tissue is preferably performed using Hounsfield units. 19 The brown and / or beige adipose tissue Hounsfield units (HU) are determined according to the following formula: HU = -70 to 100 HU, preferably -50 to 0 HU. Those skilled in the art know that the final HU value will depend on the dose administered to the subject. The range specified above is appropriate for a dose of 0.15 g per kg of body weight.

[0095] Therefore, those skilled in the art can easily assess the localization and volume and / or surface area of ​​contrast-enhanced positive areas (indicating BAT) in every PET-CT scan using PET-CT contrast agents. Both parameters are predictive of a patient's metabolic health and outcome. By comparing the total volume and / or surface area and localization of BAT present in a patient with that of matched healthy volunteers (e.g., healthy individuals matched for age, sex, weight, ethnicity, and BMI), the prognosis of a cancer patient can be established. Higher BAT volume and / or surface area are associated with higher energy expenditure. In the case of cancer patients, higher energy expenditure by BAT correlates with poorer outcomes and increased tumor aggressiveness. The higher energy expenditure is measured by comparing the uptake ratio in BAT of matched healthy volunteers. 18It can also be detected by the increased uptake ratio of FDG to PET-CT contrast agents. This is also associated with the development of cancer cachexia, which is associated with a very poor prognosis for cancer patients. Patients with abnormal BAT volume and / or surface area and location should receive special medical attention.

[0096] In view of the above, the following additional steps are preferably carried out after carrying out the method steps a) to c) of the main aspect of the first embodiment as described above for identifying non-malignant and / or non-metastatic tissues in a cancer patient: d) The above 18 identifying areas of co-localization of positive contrast enhancement of FDG and the PET-CT contrast agent; e) 18 Although there is positive contrast enhancement of FDG, 18 identifying areas that lack co-localization of positive contrast enhancement of FDG and the PET-CT contrast agent; f) assigning the areas with co-localization identified in step d) as areas without malignancy or metastasis, and assigning the areas without co-localization identified in step e) as areas with possible malignancy or metastasis.

[0097] It is rational and therefore advantageous for steps a) to c) and f) to be performed in the specified order. Steps d) and e) may be performed in the reverse order or simultaneously. Furthermore, if only information about areas without malignancies or metastases is desired, the corresponding parts of steps e) and f) may be omitted. Similarly, if only information about areas with malignancies or metastases is desired, the corresponding parts of steps d) and f) may be omitted.

[0098] For physiological reasons, such as the brain, cardiac muscle, and urinary tract (kidneys and bladder) 18It will be clear to those skilled in the art that anatomical areas known to deposit FDG should not be assigned as tumor tissue. In addition, the accuracy of the method requires additional measures regarding tissues assigned in step f) as areas of possible malignancy or metastasis, thereby avoiding tissues affected by other reasons, such as inflammation. 18 This can optionally be further improved by eliminating the possibility of FDG deposition. It will also be apparent to those skilled in the art that PET-CT contrast agents may be detected after administration in organs such as the GI tract, myocardium, liver, urinary tract, etc., due to physiological reasons and / or normal metabolism, and therefore such areas should also not be assigned as brown and / or beige adipose tissue.

[0099] The aforementioned 18 Evaluation of PET-CT scans for co-localization of positive contrast enhancement of FDG and the PET-CT contrast agent is performed to distinguish primary tumors and / or metastases from brown and / or beige adipose tissue in the human cancer patient.

[0100] As an alternative to steps a) to c) of the above main aspect of the first embodiment, the following method is provided. The method of this specific aspect comprises: 18 1. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue by PET-CT imaging in a human cancer patient who has received prior administration of an FDG PET tracer, comprising: a') administering to said human cancer patient an oral CT contrast agent comprising an iodinated fatty acid and / or its ester and / or salt and / or mixture according to general formula I as specified above, wherein the meaning of n and of the groups R1 and R2 are as specified above, The administration of the oral CT contrast agent 18 performed at least 3 hours prior to administration of the FDG PET tracer; b') 18 administering FDG to said human cancer patient according to standard practice; c') for the human cancer patient 18performing an FDG PET-CT scan; d') detecting primary tumors and / or metastases from brown and / or beige tissue in said human cancer patient. 18 comparing both the PET and CT scans to assess co-localization of positive contrast enhancement of FDG and said CT contrast agent; The method includes:

[0101] In another aspect, administration of a PET-CT contrast agent prior to a PET-CT scan is adapted for non-invasive in vivo imaging, quantification, and / or monitoring of brown and / or beige adipose tissue (BAT) activity in a subject, allowing for a more accurate prognosis of the cancer being treated and resulting in a more tailored treatment. As an alternative to steps a) to c) of the above main aspect of the first embodiment, the procedure of this specific aspect comprises: a) administering a PET-CT imaging agent as described below, for example comprising a biocompatible formulation of an iodinated fatty acid having 16 to 18 carbon atoms and / or its esters and / or salts and / or mixtures according to general formula I; b) by intravenous route, preferably according to standard practice (e.g., EANM guidelines 17 ), preferably at least 3 hours after administration of the PET-CT imaging agent of step a), 18 administering FDG; c) performing a PET-CT scan; d) comparing the PET-CT scan with that of a healthy individual; Complies with.

[0102] It is rational and therefore advantageous that steps a) to d) are performed in the specified order.

[0103] The acquired scans can be used to assess the presence of tumors and / or metastases and / or BAT (which are indicative of brown adipose tissue activity and / or volume and / or surface area). In some embodiments, the acquired scans can be used separately or in combination to assess the presence of tumors and / or metastases (PET) and the degree of uptake of the CT contrast agent in brown adipose tissue (which are indicative of brown adipose tissue activity and / or volume and / or surface area).

[0104] Both parameters taken separately or together are 18 It enables more accurate cancer prognosis than PET-CT using FDG tracer alone.

[0105] Therefore, steps a) to d) of the above specific embodiment can be replaced by the following further steps: e) The above 18 determining areas of co-localization of positive contrast enhancement of FDG and the PET-CT contrast agent as highly active BAT; f) There is positive contrast enhancement of the PET-CT contrast agent 18 determining an area where FDG is not present as BAT; g) assessing the prognosis of the cancer to be treated based on the results obtained in steps d), e) and f). It may be advantageous to combine

[0106] For example, in Example 3, other than the presence of contrast enhancement by the PET-CT contrast agent as described herein, 18 Evaluation of PET-CT scans for the absence of FDG uptake has been shown to allow for simple and robust detection of brown adipose tissue, increasing the sensitivity and positive predictive value of PET-CT scans for BAT.

[0107] Similarly, in Example 2, there were no positive results in BAT that could be interpreted as a false positive (metastasis). 18The FDG signal was correctly attributed to BAT and improved the specificity and positive predictive value of PET-CT scans for tumor metastasis, which was confirmed by autopsy (see Figures 2b, c and 3b, c).

[0108] As shown in the examples, the above-described methods of the present invention surprisingly help to improve the specificity and positive predictive value of PET-CT scans for tumor metastasis.

[0109] A still further object of the present invention is the use of a PET-CT contrast agent as described below in a PET-CT imaging method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue in human cancer patients, comprising: a') administering said oral PET-CT imaging agent to said human cancer patient, preferably by oral route, or optionally by other routes (intravenous, intrathecal, intralymphatic, intraarterial, intraperitoneal or subcutaneous); b') at least 3 hours after administration of the PET-CT contrast agent of step a), 18 administering an FDG PET tracer; c') administering to the human cancer patient 18 Colocalization of positive contrast enhancement between FDG and the above PET-CT contrast agents 18 The process of performing FDG PET-CT scan The present invention relates to use in a method comprising the steps of:

[0110] It is rational and therefore advantageous that steps a') to c') are performed in the specified order.

[0111] The aforementioned 18 Evaluation of PET-CT scans for co-localization of positive contrast enhancement of FDG and the PET-CT contrast agent is performed to distinguish primary tumors and / or metastases from brown and / or beige adipose tissue in the human cancer patient. Primary tumors and / or metastases are typically 18 are identified by FDG-positive areas, whereas brown and / or beige adipose tissue is typically18 It is identified by colocalization of FDG and PET-CT contrast signals or positive PET-CT contrast enhancement.

[0112] (ii) for the purpose of diagnosing or staging or restaging, assessing the efficacy of a therapy, or assessing the progression of cancer; The PET-CT scan may be prescribed for diagnosing or staging cancer, for assessing the efficacy of therapy, for assessing the progression of cancer, or for any reason deemed relevant to the treating oncologist or physician. 18 If FDG and PET-CT contrast agents colocalize, this 18 This means that FDG was taken up by brown adipose tissue. 18 If the FDG signal does not colocalize with the PET-CT contrast agent described in this invention, it is due to brown or beige adipose tissue. 18 FDG uptake can be easily and definitively excluded. Surprisingly, this reduces false positives for tumors and metastases. 18 Increases the specificity and positive predictive value of FDG PET-CT scans. 18 The sensitivity and negative predictive value of FDG PET-CT scans are increased by reducing false negatives.

[0113] Those skilled in the art can assess both tumor progression and cancer prognosis from a single PET-CT scan using, for example, the PET-CT contrast agent described herein according to the present invention. As previously mentioned, the patient is first administered the PET-CT contrast agent, preferably by oral route. Then, between 3 and 72 hours, preferably between 10 and 48 hours, and more preferably between 16 and 30 hours later, the patient begins the PET-CT scanning procedure. 18A radioactive tracer such as FDG is injected intravenously. Approximately 60 minutes later, the patient undergoes a PET-CT scan. A skilled artisan can obtain several pieces of information from this PET-CT scan. First, tumor progression. From the PET signal, a physician can assess, for example, whether the volume and / or surface area of ​​the tumor has been altered, and whether the number and volume and / or surface area of ​​metastases have changed compared to the PET signal from an earlier PET-CT scan.

[0114] In view of the above, the following additional steps are preferably carried out after carrying out the method steps a) to c) of the main aspect of the first embodiment as described above for cancer diagnosis: d) 18 Although there is positive contrast enhancement of FDG, 18 identifying areas that lack co-localization of positive contrast enhancement of FDG and the PET-CT contrast agent; e) 18 assigning areas with positive FDG enhancement but no co-localized positive enhancement as areas of possible malignancy or metastasis; f) Diagnosing cancer by assessing the localization of the area identified in step e).

[0115] It is rational and therefore advantageous that steps a) to f) are performed in the specified order.

[0116] As noted above, the potential areas identified in step e) may be redesigned for other reasons as outlined in more detail above. 18 It is possible to increase the accuracy of the method by taking additional measures that make it possible to eliminate the possibility of FDG deposition.

[0117] In view of the above, the following additional steps are preferably carried out after carrying out the method steps a) to c) of the main aspect of the first embodiment as described above for staging or restaging a tumor: d) 18 Although there is positive contrast enhancement of FDG, 18identifying areas that lack co-localization of positive contrast enhancement of FDG and the PET-CT contrast agent; e) 18 Although there is positive contrast enhancement of FDG, 18 assigning areas lacking co-localization of positive contrast enhancement of FDG and the PET-CT contrast agent as areas likely to contain malignant tumors or metastases; f) Allocating the patient to an appropriate stage in the TNM system by assessing the location and volume and / or surface area of ​​the possible areas identified in step e), lymph node involvement and / or the presence of metastases.

[0118] It is rational and therefore advantageous that steps a) to f) are performed in the specified order.

[0119] For cancer restaging, the above method comprising steps a) to f) is carried out on a patient who has already been subjected to earlier cancer staging using either the method described above or an alternative cancer staging method.

[0120] As noted above, the potential areas identified in step e) may be redesigned for other reasons as outlined in more detail above. 18 It is possible to increase the accuracy of the method by taking additional measures that make it possible to eliminate the possibility of FDG deposition.

[0121] In view of the above, the following additional steps are preferably carried out after carrying out the method steps a) to c) of the main aspect of the first embodiment as described above for assessing the efficacy of a therapy or assessing the progression of a cancer: d) 18 Although there is positive contrast enhancement of FDG, 18 identifying areas lacking co-localization of positive contrast enhancement of FDG and the PET-CT contrast agent as areas likely to harbor malignant tumors or metastases; e) 18determining the volume and / or surface area of ​​identified areas with positive FDG contrast enhancement but without co-localized positive contrast enhancement; f) optionally subjecting the patient to anti-cancer therapy; g) repeating steps a) to e); h) assigning an effective therapy, if performed, and / or a lack of cancer progression, if the volume and / or surface area of ​​the area identified according to step g) is equal to or smaller than the volume and / or surface area of ​​the area identified according to step e), and assigning an ineffective therapy, if performed, and / or a lack of cancer progression, if the volume and / or surface area of ​​the area identified according to step g) is greater than the volume and / or surface area of ​​the area identified according to step e).

[0122] It is reasonable and therefore advantageous for steps a) to e) to be performed in the specified order. Similarly, the repeated steps a) to e) as summarized in step g) are also advantageously performed in the specified order. Step h) should be performed as the final step. However, there are no restrictions regarding the relative order of steps d) and e) with respect to the repeated steps d) and e) as summarized in step g).

[0123] As noted above, for any potential areas identified in the iterative process in step d) and item g), for other reasons as outlined in more detail above. 18 It is possible to increase the accuracy of the method by taking additional measures that make it possible to eliminate the possibility of FDG deposition.

[0124] (iii) Determining BAT activity and / or cancer prognosis 18 Poorer outcomes are usually observed in cancer patients with highly active brown adipose tissue, characterized by FDG uptake 13 In these patients, the more metabolically active brown adipose tissue ( 18Higher BAT volume and / or surface area were associated with an increased likelihood of tumor recurrence and / or tumor-related mortality. 14 This may be related not only to tumor severity (inflammatory and tumor factors that promote brown adipose tissue activation and white adipose tissue browning) but also to the incidence of cachexia, a fatal body-wasting syndrome associated with cancer and chronic disease.

[0125] As mentioned earlier, in brown adipose tissue 18 FDG uptake is 18 It is observed in approximately 5% of patients undergoing FDG PET-CT scans. Information about the volume and / or surface area of ​​brown adipose tissue and its level of activation would provide cancer patients' caregivers with valuable information regarding cancer prognosis. This can be achieved by using the PET-CT contrast agents described in this invention during planned diagnostic and / or staging PET-CT scans prescribed by an oncologist or another physician.

[0126] In view of the above, the following additional steps are preferably carried out after carrying out the method steps a) to c) of the main aspect of the first embodiment as described above for determining BAT activity: d) The above 18 identifying areas of co-localized positive contrast enhancement of FDG and the PET-CT contrast agent, as well as areas of positive contrast enhancement of the PET-CT contrast agent alone; e) the compound as identified in step d). 18 determining the volume and / or surface area of ​​areas where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; f) determining the volume and / or surface area of ​​the area with positive contrast enhancement of only said PET-CT contrast agent as identified in step d); g) calculating the ratio of the volume and / or surface area determined in step e) divided by the volume and / or surface area determined in step f); h) comparing the ratio with a reference ratio determined as an average value by carrying out steps a) to g) on ​​a population of cancer patients; i) assigning increased BAT activity if the determined ratio is higher than the reference ratio, assigning normal or reduced BAT activity if the determined ratio is approximately the same as the reference ratio, and assigning reduced BAT activity if the determined ratio is lower than the reference ratio.

[0127] It is reasonable, and therefore advantageous, for steps a) to i) to be performed in the specified order, except for steps e) and f), which may be performed simultaneously or in reverse order.

[0128] To determine the prognosis of cancer, the same steps a) to i) as described above for determining BAT activity can be performed. Subsequently, the following step j) can be added to obtain the prognosis: j) assigning a poor prognosis if step i) assigns decreased BAT activity in the patient suffering from hormone-dependent cancer and assigning a poor prognosis if step i) assigns increased BAT activity in the patient suffering from hormone-independent cancer.

[0129] The addition of PET-CT contrast agents, described below, allows for more accurate prognosis of cancer progression and outcome, depending on the degree of contrast uptake in brown adipose tissue and the volume and / or surface area of ​​brown adipose tissue. 18 Increased FDG uptake indicates a poorer cancer prognosis.

[0130] In yet another specific variant of this object of the present invention, there is provided a prognostic method for cancer assessment in human cancer patients by assessing the amount of activated brown and / or beige adipose tissue by PET-CT imaging, the method comprising steps a) to c) of the main aspect of the first embodiment as described above, or alternatively, a) administering to said cancer patient a PET-CT imaging agent as described herein, wherein administering said PET-CT imaging agent comprises: 18 performed at least 3 hours prior to administration of FDG; b) by the intravenous route, preferably according to standard practice, e.g. 17 As described in 18 administering FDG; c) performing a PET-CT scan on the human cancer patient; Includes:

[0131] In this method, uptake of the PET-CT contrast agent by brown adipose tissue can be taken as the basis for determining cancer prognosis. In some embodiments of the present invention, uptake of the PET-CT contrast agent by brown adipose tissue can be compared to baseline values ​​for healthy patients with matched relevant characteristics (e.g., healthy individuals matched for age, sex, weight, ethnicity, and BMI). For most cancer types, a poor prognosis can be identified for human cancer patients with higher uptake, i.e., larger areas of positive contrast enhancement, compared to baseline values. For other malignancies (e.g., hormonally influenced cancers such as some breast cancers), higher uptake indicates a better cancer outcome.

[0132] In view of the above, the following additional steps are preferably carried out after carrying out steps a) to c) of the main aspect of the first embodiment as described above: d) The above 18 determining the volume and / or surface area of ​​the area of ​​positive contrast enhancement where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; e) comparing the determined volume and / or surface area with a reference value determined as an average value by carrying out steps a) to d) on a population of cancer patients; f) assigning a poor prognosis if the quantified volume and / or surface area is lower than the reference value in patients with hormone-dependent cancer, and assigning a poor prognosis if the quantified volume and / or surface area is higher than the reference value in patients with hormone-independent cancer.

[0133] It is rational and therefore advantageous that steps a) to f) are performed in the specified order.

[0134] In another variant, taking the above into consideration, all BAT can be used as a basis for prognosis. In this variant, the following additional steps are preferably carried out after carrying out steps a) to c) of the main aspect of the first embodiment as described above: d) determining the volume and / or surface area of ​​positive contrast enhancement of the PET-CT contrast agent; e) comparing the determined volume and / or surface area with reference values ​​derived from a healthy individual or a group of healthy individuals; f) assigning a poor prognosis if the quantified volume and / or surface area is lower than the reference value in patients with hormone-dependent cancer, and assigning a poor prognosis if the quantified volume and / or surface area is higher than the reference value in patients with hormone-independent cancer.

[0135] It is rational and therefore advantageous that steps a) to f) are performed in the specified order.

[0136] The accuracy of the prognosis can be determined by performing the above steps a) to f) in addition to the following steps: g) The above 18 determining areas without co-localization of positive contrast enhancement of FDG and the PET-CT contrast agent as possible tumors or metastases; h) assigning a prognosis based on the outcome of step f) and additionally based on the volume and / or surface area and / or location of the tumor or metastasis based on the determination of step g). It can be improved by combining it with

[0137] For example, in step h), a factor contributing to a poor prognosis is the spread of the tissue identified in step g) to distant lymph nodes and / or the identification of multiple metastases.

[0138] As noted above, the potential areas identified in step g) may be redesigned for other reasons as outlined in more detail above. 18 It is possible to increase the accuracy of the method by taking additional measures that make it possible to eliminate the possibility of FDG deposition.

[0139] The PET-CT scan may be prescribed for tumor detection, diagnosis or staging, to assess the efficacy of therapy, to assess the progression of cancer, or for any reason deemed relevant to the treating oncologist or physician.

[0140] In a first embodiment, the cancer is preferably a cancer involving malignant tumors, more preferably selected from the group comprising or consisting of lung, colorectal, breast, gynecological, head and neck, esophageal, gastric, biliary tract, follicular and medullary thyroid, and pancreatic cancer, leukemia, melanoma, lymphoma, multiple myeloma, sarcoma, primary brain tumor, pheochromocytoma, lipoma, or liposarcoma.

[0141] The method of the second embodiment of the present invention Advantageously, the PET-CT imaging agents described below can also be used in human subjects who do not have cancer but who suffer from metabolic diseases such as obesity or diabetes, or in healthy volunteers.

[0142] Therefore, a further object of the present invention is a method for identifying a metabolic disease in a human subject by PET-CT imaging of brown and / or beige adipose tissue in said human subject, comprising: a) administering to said human subject a PET-CT imaging agent as described below; b) at least 3 hours after administration of the PET-CT contrast agent of step a), 18administering an FDG PET tracer; c) to said human subject 18 The process of performing FDG PET-CT scan The object of the present invention is to provide a method comprising:

[0143] The presence of a metabolic disease may be identified, for example, by quantifying the positive contrast enhancement and comparing the determined value with a reference value for healthy individuals, and if the quantified positive contrast enhancement shows a deviation from the reference value for healthy individuals, this may be interpreted as an indication of the presence of a metabolic disease. The reference value for healthy individuals may be derived by performing the above procedure using steps a) to c) and, if applicable, averaging values ​​obtained from a healthy individual or a cohort of healthy individuals with matching relevant characteristics (e.g., healthy individuals matched for age, sex, ethnicity, weight, BMI).

[0144] For example, the uptake of PET-CT contrast agents reflects the amount of BAT present in a subject. A higher amount of BAT is associated with lower blood glucose, cholesterol (LDL), triglycerides, and free fatty acids, as well as better insulin sensitivity. In contrast, the absence or low volume and / or surface area of ​​BAT is associated with an inadequate metabolic state, i.e., high blood levels of hyperglycemia, cholesterol (LDL), triglycerides, and free fatty acids, as well as low insulin sensitivity. Obese patients with adequate BAT have a much better metabolic state than obese patients with low or absent BAT. The second category of patients requires special medical attention and care, including nutritional intervention to adjust their calorie intake and a personalized exercise program. They should also undergo additional diagnostic procedures to evaluate whether they have NAFLD and / or NASH, and appropriate treatment, if necessary.

[0145] In view of the above, the following additional steps are preferably carried out after carrying out the method described above: d) quantifying the volume and / or surface area of ​​positive contrast enhancement of the PET-CT contrast agent in the PET-CT scan of step c); e) comparing the quantified volume and / or surface area of ​​step d) with reference values ​​derived from one or more healthy individuals; f) assigning a poor metabolic state if the quantified volume and / or surface area is lower than the reference value and a good metabolic state if the quantified volume and / or surface area is equal to or higher than the reference value.

[0146] It is rational and therefore advantageous for steps a) to f) of this method to be carried out in the specified order.

[0147] Those skilled in the art can judge the reliability of such determinations based on the degree of deviation and measurement error.

[0148] According to one embodiment, the human subject suffers from obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0149] According to another embodiment, the human subject is a subject who does not have cancer.

[0150] In the above methods, the reference values ​​are preferably derived from healthy individuals who are matched to the patient with respect to age range, sex, ethnicity, body mass range and / or BMI range.

[0151] The method of the third embodiment of the present invention It is also envisioned that the PET-CT imaging agents and methods of the invention described below will be used as companion diagnostics in clinical or preclinical studies to help develop new therapies for metabolic diseases, or to select patients who may benefit from these therapies, or to evaluate the efficacy of said therapies in human or animal subjects.

[0152] For example, some researchers aim to develop treatments for obesity by activating BAT and / or inducing the conversion of WAT to BAT. These researchers could generally benefit from using the imaging agents described below to assess the efficacy of the treatment early. On the other hand, those developing anti-cancer therapies may want to screen potential study subjects to avoid patients who develop cachexia or to divide patients into subgroups with and without cachexia to assess treatment efficacy. This can be done by performing a PET-CT scan using an imaging agent to assess the volume and / or surface area of ​​BAT in each subject during screening. Researchers developing treatments for cachexia may want to start treatment as early as possible, ideally before weight loss. Similarly, patient screening can be performed using a PET-CT imaging agent to assess the volume and / or surface area of ​​BAT in each cancer patient. In all of these examples, volunteers and / or patients may 1) a PET-CT imaging agent as described below, preferably administered by the oral route; 2) After at least 3 hours, 18 FDG or another PET tracer is administered. 3) 18 FDG PET-CT scan, or if another PET tracer is used, a PET-CT scan appropriate for said other PET tracer, preferably as described in e.g. 17 The patient was subjected to standard protocols as described in It would be.

[0153] The investigator can then assess the volume and / or surface area and / or location of BAT and compare it to that of a healthy individual with matched relevant characteristics (e.g., a healthy person matched for age, sex, weight, ethnicity, BMI). These characteristics may include, but are not limited to, sex, age, weight, ethnicity, and BMI. Volunteers and / or patients may be used as their own controls to assess the efficacy of treatment.

[0154] Thus, when developing a treatment for obesity and / or type 2 diabetes, a patient's PET-CT scan after one or more administrations of the treatment may be compared with the patient's PET-CT scan before the treatment. Efficacy of the treatment can be confirmed if BAT volume and / or surface area increases. An increase in active BAT volume and / or surface area can also indicate efficacy, as can an increase in the ratio of active BAT to total BAT. Alternatively, the efficacy of such a treatment can be assessed by adding a placebo arm of test subjects and performing steps 1) to 3) above on the placebo group subjects to establish that the above-mentioned effect of BAT increase is not observed or is observed to a lesser extent in the placebo group.

[0155] In view of the above, the present invention provides a method for assessing the efficacy of a treatment for obesity and / or type 2 diabetes, focusing on the amount of active BAT, comprising the steps of: 1) administering a PET-CT imaging agent as described below prior to administration of an obesity and / or type 2 diabetes treatment; 2) After at least 3 hours, 18 administering FDG; 3) 18 performing an FDG PET-CT scan; 4) administering one or more obesity and / or type 2 diabetes treatments; 5) administering a PET-CT imaging agent as described below after administration of the obesity and / or type 2 diabetes treatment; 6) After at least 3 hours, 18 administering FDG; 7) 18 performing an FDG PET-CT scan; 8) In the PET-CT scan of step 3), 18 determining the volume and / or surface area of ​​areas where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; 9) In the PET-CT scan of step 7), 18 determining the volume and / or surface area of ​​areas where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; 10) comparing the volume and / or surface area determined in step 8) with the volume and / or surface area determined in step 9); 11) assigning efficacy of obesity and / or type 2 diabetes treatment if the comparison of step 10) indicates an increase in volume and / or surface area from step 8) to step 9). A first variant of the method is provided, comprising:

[0156] The method can be performed on a single patient or preferably on a group of patients. In the case where the method is performed on a group of patients, the results for the individual patients can be evaluated together to reduce statistical error.

[0157] In the above method, it is reasonable, and therefore advantageous, that steps 1) to 7) are performed in the specified order, while steps 8) and 9) may be performed in the reverse order or simultaneously.

[0158] In a variation that relies on a placebo control, the method comprises the following steps: 1) administering a PET-CT imaging agent as described below to a patient or group of patients prior to administration of an obesity and / or type 2 diabetes treatment; 2) After at least 3 hours, 18 administering FDG; 3) 18 performing an FDG PET-CT scan; 4) administering one or more obesity and / or type 2 diabetes treatments; 5) administering a PET-CT imaging agent as described below to the patient after administration of an obesity and / or type 2 diabetes treatment; 6) After at least 3 hours, 18 administering FDG; 7) 18performing an FDG PET-CT scan; 8) In the PET-CT scan of step 3), 18 determining the volume and / or surface area of ​​areas where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; 9) In the PET-CT scan of step 7), 18 determining the volume and / or surface area of ​​areas where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; 10) comparing the volume and / or surface area determined in step 8) with the volume and / or surface area determined in step 9); 11) performing steps 1) to 10) on a different patient or group of patients, but administering a placebo treatment instead of the obesity and / or type 2 diabetes treatment in step 4; 12) assigning efficacy of the obesity and / or type 2 diabetes treatment if the comparison of step 10) in the obesity and / or type 2 diabetes treated patient or patient group shows a greater increase in volume and / or surface area from step 8) to step 9) than that obtained in the comparison of step 10) in the placebo patient or patient group. Includes:

[0159] In the above method, it is reasonable and therefore advantageous that steps 1) to 7) are performed in the specified order, while steps 8) and 9) may be performed in the reverse order or simultaneously. The same applies to the corresponding step grouped as step 11). The step grouped as step 11) may be performed before, simultaneously with, or after steps 1) to 10).

[0160] The present invention provides a method for assessing the efficacy of a treatment for obesity and / or type 2 diabetes, focusing on the amount of total BAT, comprising the following steps: 1) administering a PET-CT imaging agent as described below prior to administration of an obesity and / or type 2 diabetes treatment; 2) After at least 3 hours, 18 administering FDG; 3) 18 performing an FDG PET-CT scan; 4) administering one or more obesity and / or type 2 diabetes treatments; 5) administering a PET-CT imaging agent as described below after administration of the obesity and / or type 2 diabetes treatment; 6) After at least 3 hours, 18 administering FDG; 7) 18 performing an FDG PET-CT scan; 8) determining the volume and / or surface area of ​​the area with positive contrast enhancement of said PET-CT contrast agent in the PET-CT scan of step 3); 9) determining the volume and / or surface area of ​​the area with positive contrast enhancement of said PET-CT contrast agent in the PET-CT scan of step 7); 10) comparing the volume and / or surface area determined in step 8) with the volume and / or surface area determined in step 9); 11) assigning efficacy for treating obesity and / or type 2 diabetes if the comparison of step 10) indicates an increase in volume and / or surface area from step 8) to step 9). There is further provided a second variant of the method, comprising:

[0161] In the above method, it is reasonable, and therefore advantageous, that steps 1) to 7) are performed in the specified order, while steps 8) and 9) may be performed in the reverse order or simultaneously.

[0162] In a variation that focuses on all BAT and relies on a placebo control, the method comprises the following steps: 1) administering a PET-CT imaging agent as described below to a patient or group of patients prior to administration of an obesity and / or type 2 diabetes treatment; 2) After at least 3 hours, 18 administering FDG; 3) 18performing an FDG PET-CT scan; 4) administering one or more obesity and / or type 2 diabetes treatments; 5) administering a PET-CT imaging agent as described below to the patient after administration of an obesity and / or type 2 diabetes treatment; 6) After at least 3 hours, 18 administering FDG; 7) 18 performing an FDG PET-CT scan; 8) determining the volume and / or surface area of ​​the area with positive contrast enhancement of said PET-CT contrast agent in the PET-CT scan of step 3); 9) determining the volume and / or surface area of ​​the area with positive contrast enhancement of said PET-CT contrast agent in the PET-CT scan of step 7); 10) comparing the volume and / or surface area determined in step 8) with the volume and / or surface area determined in step 9); 11) performing steps 1) to 10) on a different patient or group of patients, but administering a placebo treatment instead of the obesity and / or type 2 diabetes treatment in step 4; 12) assigning efficacy of the obesity and / or type 2 diabetes treatment if the comparison of step 10) in the obesity and / or type 2 diabetes treated patient or patient group shows a greater increase in volume and / or surface area from step 8) to step 9) than that obtained in the comparison of step 10) in the placebo patient or patient group. Includes:

[0163] In the above method, it is reasonable and therefore advantageous that steps 1) to 7) are performed in the specified order, while steps 8) and 9) may be performed in the reverse order or simultaneously. The same applies to the corresponding step grouped as step 11). The step grouped as step 11) may be performed before, simultaneously with, or after steps 1) to 10).

[0164] The present invention provides a method for assessing the efficacy of a treatment for obesity and / or type 2 diabetes, focusing on the ratio of the amount of active BAT to the amount of total BAT, comprising the following steps: 1) administering a PET-CT imaging agent as described below prior to administration of an obesity and / or type 2 diabetes treatment; 2) After at least 3 hours, 18 administering FDG; 3) 18 performing an FDG PET-CT scan; 4) administering one or more obesity and / or type 2 diabetes treatments; 5) administering a PET-CT imaging agent as described below after administration of the obesity and / or type 2 diabetes treatment; 6) After at least 3 hours, 18 administering FDG; 7) 18 performing an FDG PET-CT scan; 8) In the PET-CT scan of step 3), 18 determining the volume and / or surface area of ​​areas where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; 9) In the PET-CT scan of step 7), 18 determining the volume and / or surface area of ​​areas where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; 10) determining the volume and / or surface area of ​​the area with positive contrast enhancement of said PET-CT contrast agent in the PET-CT scan of step 3); 11) determining the volume and / or surface area of ​​the area with positive contrast enhancement of said PET-CT contrast agent in the PET-CT scan of step 7); 12) calculating a first ratio by dividing the volume and / or surface area determined in step 8) by the volume and / or surface area in step 10); 13) calculating a second ratio by dividing the volume and / or surface area determined in step 9) by the volume and / or surface area in step 11); 14) comparing the ratio determined in step 12) with the ratio determined in step 13); 15) assigning efficacy of treatment for obesity and / or type 2 diabetes if the comparison of step 14) shows an increase in the ratio from step 12) to step 13). There is further provided a third variation of the method, comprising:

[0165] In the above method, it is reasonable, and therefore advantageous, that steps 1) to 7) are carried out in the specified order, while steps 8) to 11) and similarly steps 12) and 13) may be carried out in the reverse order or simultaneously.

[0166] In a variation that focuses on the ratio of active BAT to total BAT and relies on a placebo control, the method comprises the following steps: 1) administering a PET-CT imaging agent as described below to a patient or group of patients prior to administration of an obesity and / or type 2 diabetes treatment; 2) After at least 3 hours, 18 administering FDG; 3) 18 performing an FDG PET-CT scan; 4) administering one or more obesity and / or type 2 diabetes treatments; 5) administering a PET-CT imaging agent as described below to the patient after administration of an obesity and / or type 2 diabetes treatment; 6) After at least 3 hours, 18 administering FDG; 7) 18 performing an FDG PET-CT scan; 8) In the PET-CT scan of step 3), 18 determining the volume and / or surface area of ​​areas where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; 9) In the PET-CT scan of step 7), 18determining the volume and / or surface area of ​​areas where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; 10) determining the volume and / or surface area of ​​the area with positive contrast enhancement of said PET-CT contrast agent in the PET-CT scan of step 3); 11) determining the volume and / or surface area of ​​the area with positive contrast enhancement of said PET-CT contrast agent in the PET-CT scan of step 7); 12) calculating a first ratio by dividing the volume and / or surface area determined in step 8) by the volume and / or surface area in step 10); 13) calculating a second ratio by dividing the volume and / or surface area determined in step 9) by the volume and / or surface area in step 11); 14) comparing the ratio determined in step 12) with the volume and / or surface area determined in step 13); 15) performing steps 1) to 14) on a different patient or group of patients, except that in step 4, a placebo treatment is administered instead of the obesity and / or type 2 diabetes treatment; 16) assigning efficacy of the obesity and / or type 2 diabetes treatment if the comparison of step 14) in the obesity and / or type 2 diabetes treated patient or patient group shows an increase in the ratio from step 12) to step 13) that is greater than that obtained in the comparison of step 14) in the placebo patient or patient group. Includes:

[0167] In the above method, it is reasonable and therefore advantageous that steps 1) to 7) are performed in the specified order, while steps 8) to 11) and likewise steps 12) and 13) may be performed in the reverse order or simultaneously. The same applies to the corresponding step grouped under step 15). The step grouped under step 15) may be performed before, simultaneously with, or after steps 1) to 14).

[0168] A similar approach can be taken when evaluating the efficacy of anti-cancer therapy under development. That is, the PET-CT scan of a patient after one or more anti-cancer treatments can be compared with the PET-CT scan of the patient before treatment. The efficacy of the treatment can be confirmed if one or more of the following parameters are reduced after treatment: tumor size, number of metastases, and / or BAT activity. Alternatively, the PET-CT scan of one or more patients after one or more anti-cancer treatments can be compared with the PET-CT scan of one or more patients who receive placebo or preferably standard treatment. The efficacy of the treatment can be confirmed if one or more of the following parameters are reduced in the test group compared with the placebo or reference group: tumor size, number of metastases, and / or BAT activity.

[0169] In view of the above, the present invention provides a method for assessing the efficacy of an anti-cancer treatment, comprising the steps of: 1) administering a PET-CT imaging agent as described below prior to administration of an anti-cancer treatment; 2) After at least 3 hours, 18 administering FDG; 3) 18 performing an FDG PET-CT scan; 4) administering one or more anti-cancer treatments; 5) administering a PET-CT imaging agent as described below after the anti-cancer treatment; 6) After at least 3 hours, 18 administering FDG; 7) 18 performing an FDG PET-CT scan; 8) In the PET-CT scan of step 3) 18 determining the volume and / or surface area of ​​areas with positive FDG contrast enhancement but without co-localized positive contrast enhancement; 9) In the PET-CT scan of step 7) 18 determining the volume and / or surface area of ​​areas with positive FDG contrast enhancement but without co-localized positive contrast enhancement; 10) comparing the volume and / or surface area determined in step 8) with the volume and / or surface area determined in step 9); 11) assigning efficacy of anti-cancer treatment if the comparison of step 10) does not show an increase in volume and / or surface area from step 8) to step 9). A first variant of the method is provided, comprising:

[0170] The method can be performed on a single patient or, preferably, on a group of patients, in which case the results for the individual patients can be evaluated together to reduce statistical error.

[0171] In the above method, it is reasonable, and therefore advantageous, that steps 1) to 7) are performed in the specified order, while steps 8) and 9) may be performed in the reverse order or simultaneously.

[0172] In a variation that relies on a placebo or preferably reference treatment control, the method comprises the following steps: 1) administering a PET-CT imaging agent as described below to a patient or group of patients prior to administration of an anti-cancer treatment; 2) After at least 3 hours, 18 administering FDG; 3) 18 performing an FDG PET-CT scan; 4) administering one or more anti-cancer treatments; 5) administering a PET-CT imaging agent as described below to the patient after the anti-cancer treatment; 6) After at least 3 hours, 18 administering FDG; 7) 18 performing an FDG PET-CT scan; 8) In the PET-CT scan of step 3) 18 determining the volume and / or surface area of ​​areas with positive FDG contrast enhancement but without co-localized positive contrast enhancement; 9) In the PET-CT scan of step 7)18 determining the volume and / or surface area of ​​areas with positive FDG contrast enhancement but without co-localized positive contrast enhancement; 10) comparing the volume and / or surface area determined in step 8) with the volume and / or surface area determined in step 9); 11) performing steps 1) to 10) on a different patient or group of patients, except that in step 4 a placebo or reference treatment is administered instead of the anti-cancer treatment; 12) assigning efficacy of the anti-cancer treatment if the comparison of step 10) in the anti-cancer treated patient or patient group shows an increase in volume and / or surface area from step 8) to step 9) that is less than that obtained in the comparison of step 10) in the placebo patient or patient group, or, if a reference treatment is used in step 11), assigning efficacy of the anti-cancer treatment if the comparison of step 10) in the anti-cancer treated patient or patient group shows an increase in volume and / or surface area from step 8) to step 9) that is less than or equal to that obtained in the comparison of step 10) in the patient or patient group receiving the reference treatment. Includes:

[0173] In the above method, it is reasonable and therefore advantageous that steps 1) to 7) are performed in the specified order, while steps 8) and 9) may be performed in the reverse order or simultaneously. The same applies to the corresponding step grouped as step 11). The step grouped as step 11) may be performed before, simultaneously with, or after steps 1) to 10).

[0174] Procedural aspects common to all methods of the present invention In step c) 18 The FDG PET-CT scan or other PET-CT scan is preferably performed 6 to 72 hours, more preferably 8 to 48 hours, and even more preferably 16 to 30 hours after administration of the PET-CT contrast agent in step a). 18 FDG PET-CT scan or other PET-CT scan in step b) 18It is preferably performed 30 to 120 minutes, preferably 45 to 75 minutes, more preferably 55 to 65 minutes after administration of FDG or other radioactive tracer.

[0175] According to an embodiment, administration of the PET-CT contrast agent occurs the day before the planned PET-CT scan. Preferably, administration of the PET-CT contrast agent occurs the day before the planned PET-CT scan. 18 It is performed at least 3 hours, such as at least 4 hours, or at least 6 hours, or at least 10 hours, especially 3 to 72 hours, more preferably 10 to 48 hours, even more preferably 16 to 30 hours, before administration of FDG or other PET tracer.

[0176] Preferably, the PET-CT imaging agent is administered orally (i.e., via the oral route). The PET-CT imaging agent is preferably given to the patient via the oral route, but may also be administered by other routes (intravenous, intrathecal, intralymphatic, intraarterial, intraperitoneal, subcutaneous).

[0177] In a preferred embodiment of the present invention, the PET-CT images are sagittal or coronal. Sagittal or coronal views are preferred because they avoid time- and resource-consuming evaluation of axial slices of the PET-CT scan by radiologists and / or nuclear medicine physicians.

[0178] In another embodiment of the invention, the evaluation of PET-CT scans is performed by software or a plug-in or add-in or add-on to existing software.

[0179] Preferably, the software analysis is performed by machine learning such as ANN, RNN, DL or CNN techniques.

[0180] In a preferred embodiment, the method of the present invention is adapted for use in human patients, in particular human cancer patients, said human patients / human cancer patients being under 18 years of age.

[0181] Active Agents of PET-CT Contrast Agents for Use in the Present Invention The PET-CT imaging agent for use in the present invention comprises, as the active imaging agent, one or more iodinated fatty acids and / or esters and / or salts and / or mixtures thereof, which preferably have the general formula I:

[0182] [ka] (wherein n=14 to 16, each R1 is independently selected from H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is selected from H, unsaturated or saturated, linear or branched alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, polyalkyleneoxyalkyl, hydroxypolyalkyleneoxyalkyl, aryl, aryloxy, arylcarbonyl, arylcarbonylalkyl, heteroaryl, non-aromatic heterocycle, or alkylcarbonyloxyalkyl, which are optionally substituted with one or more, preferably 1 to 5, more preferably 1, 2, 3, or 4, substituents each independently selected from aryl, heteroaryl, halogen, hydroxy, alkyl, alkoxy, aryloxy, and non-aromatic heterocycle. Each of these halogen substituents may be independently selected from F, Cl, Br, and I. When multiple iodine atoms are present, the same provisos as defined herein for the R1 group apply, i.e., there cannot be two iodine atoms in either geminal or vicinal positions. It is a compound according to the following:

[0183] Preferably, the R2 group may be mono- or polysubstituted.

[0184] Preferred R groups are alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropylmethyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, 2-propenyl, allyl, crotyl, 1-butenyl, 2-butenyl, butadienyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and propargyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl; aryl groups, such as phenyl, naphthyl, Examples of suitable alkyl groups include, but are not limited to, anisyl, toluyl, xylenyl, aralkyl, aralkyloxy, heteroaryl groups, such as pyrimidine, morpholine, piperazine, piperidine, and thiophene, 1-cyclohexylpropyl, or haloalkyl groups, such as fluoromethyl, 1-fluoroethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, and pentafluoroethyl, chlorodimethyl, chloromethyl, 2-chloroethyl, 2,4-dichlorophenyl, 1,1,2,2-tetrachloroethyl, 1-chlorobutyl, and 4-chlorobenzyl.

[0185] This can include substituted alkyl groups such as 9-fluorenylmethyl, polyalkyleneoxyalkyl groups such as methoxyethoxymethyl, non-aromatic heterocycles such as tetrahydropyranyl, optionally substituted alkylcarbonyloxyalkyl groups such as pivalyloxymethyl and phenylacetoxymethyl, optionally substituted arylcarbonyl groups such as phenacyl and substituted phenacyl, such as p-bromophenacyl, p-methoxyphenacyl, and also substituted and unsubstituted alkyl or alkenyl groups such as t-butyl, 3-methyl-3-pentyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, cinnamyl, and heteroaryl groups such as oxazole and 2-alkyl-1,3-oxazoline.

[0186] This may include alkylaryl, such as benzyl, substituted benzyl, for example, triphenylmethyl, p-methoxybenzyl, 4-picolyl, diphenylmethyl, phenylethyl, substituted phenylethyl, as well as alkoxyalkyl, for example, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, isobutoxyethyl, hydroxyalkoxyalkyl, for example, hydroxymethoxymethyl, 2-hydroxyethoxymethyl, 3-hydroxypropoxymethyl, 4-hydroxybutoxymethyl, hydroxymethoxyethyl, hydroxymethoxypropyl, hydroxymethoxybutyl, hydroxymethoxypentyl, hydroxymethoxyhexyl, polyhydroxyalkyl and hydroxypolyalkyleneoxyalkyl, and also carbonyloxyalkyl, for example, acetoyloxymethyl, propanoyloxymethyl, butanoyloxymethyl, pentanoyloxymethyl, hexanoyloxymethyl, pivaloyloxymethyl, and similar groups.

[0187] Iodinated fatty acids having 16 to 18 carbon atoms and / or esters and / or salts and / or mixtures thereof according to general formula I are, in some embodiments, characterized by one of the following sub-formulae A, B and C:

[0188] [ka] wherein n is an integer from 1 to 6, x and y are carbon atoms, x=0 to 15 and y=0 to 15 and x+y≦15, with the proviso that the total number of carbon atoms in the fatty acid moiety of formula A, B or C, respectively, is between 14 and 20, preferably between 16 and 18, each R1 is independently selected from H or I, with the proviso that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal, and the R2 groups are the same as specified above for formula I and may be mono- or polysubstituted.

[0189] Thus, suitable R groups for formula A, B or C include, for example, unsubstituted alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, and the like, as well as substituted alkyl groups, such as 9-fluorenylmethyl, methoxyethoxymethyl, tetrahydropyranyl, pivaloyloxymethyl, phenylacetoxymethyl, phenacyl, and substituted phenacyl, such as p-bromophenacyl, p-methoxyphenacyl, and also t-butyl, 3-methyl-3-pentyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1yl, cinnamyl, oxazole, 2-alkyl-1,3-oxazoline, and the like. This includes alkylaryl, such as benzyl, substituted benzyl, for example, triphenylmethyl, p-methoxybenzyl, 4-picolyl, diphenylmethylphenylethyl, substituted phenylethyl, but also alkoxyalkyl, such as methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, isobutoxyethyl, hydroxyalkoxyalkyl, such as hydroxymethoxymethyl, 2-hydroxyethoxymethyl, 3-hydroxypropoxymethyl, 4-hydroxybutoxymethyl, hydroxymethoxyethyl, hydroxymethoxypropylhydroxymethoxybutyl, hydroxymethoxypentyl, hydroxymethoxyhexyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl, and also carbonyloxyalkyl, such as acetoyloxymethyl, propanoyloxymethyl, butanoyloxymethyl, pentanoyloxymethyl, hexanoyloxymethyl, pivaloyloxymethyl, and similar groups.

[0190] The iodinated fatty acids and / or esters and / or mixtures thereof having 16 to 18 carbon atoms according to the present invention may exist as isomeric mixtures or as single isomers. Unless otherwise specified, both isomeric forms are intended. When the compounds of the present invention contain one chiral center, the iodinated compounds may be provided as a single isomer (R or S) or as a mixture of isomers, e.g., a racemic mixture. When the iodinated compounds of the present invention contain more than one chiral center, the iodinated compounds may be provided as enantiomerically pure diastereoisomers or as a mixture of diastereoisomers.

[0191] According to certain embodiments of the present invention, it is also envisaged that the PET-CT imaging agent comprises an iodinated fatty acid and / or ester thereof having 4 to 24 carbon atoms, which may be used in a mixture comprising several or at least two iodinated fatty acids having different carbon chains of 4 to 24 carbon atoms. In a preferred embodiment of the present invention, the PET-CT imaging agent comprises an iodinated fatty acid according to general formula I, preferably having 12 to 22 carbon atoms, more preferably 14 to 20, and even more preferably 16 to 18 carbon atoms.

[0192] In an even more preferred embodiment, the iodinated fatty acid is iodinated linolenic acid.

[0193] Preferably, the iodinated fatty acid is periodated.

[0194] According to a preferred embodiment, iodinated fatty acids and / or esters and / or salts and / or mixtures thereof containing 12 to 22, e.g., 12 to 20, carbon atoms, preferably 14 to 20 or more preferably 14 to 18, carbon atoms, even more preferably 16 to 18, carbon atoms may be used according to the present invention.

[0195] In another embodiment, the iodinated fatty acids and / or esters and / or mixtures thereof having 16 to 18 carbon atoms according to the present invention have at least one asymmetric center. As a result of this asymmetric center, the iodinated compounds of the present invention can occur in any of the possible stereoisomeric forms and can be used in mixtures of stereoisomers, can be optically active or racemic, or can be used singly as essentially pure stereoisomers, i.e., at least 95% pure. All asymmetric forms, individual stereoisomers, and combinations thereof are within the scope of the present invention.

[0196] According to yet another embodiment of the present invention, the PET-CT imaging agent consists of iodinated fatty acids and / or esters thereof having 16-18 carbon atoms, which may be used in mixtures containing several or at least two iodinated fatty acids having 16-18 carbon atoms. Preferably, the PET-CT imaging agent is a biocompatible emulsion of iodinated fatty acids having 16-18 carbon atoms according to general formula I:

[0197] According to another embodiment, the biocompatible formulation is a formulation of ethiodized oil.

[0198] Preparation of PET-CT contrast agent activation agent It is understood that any suitable method for preparing iodinated fatty acids having 16 to 18 carbon atoms of formula (I) and / or their esters and / or salts and / or mixtures known to those skilled in the art is within the scope of the present invention. Suitable preparation methods are described, for example, in WO2019 / 030024A1, pages 22-23 and Examples 1-15, and in WO2020 / 165349A1, pages 28-30 and Examples 1-10.

[0199] PET-CT Contrast Agents for Use in the Invention The PET-CT contrast agent is adapted for oral (ie, oral) administration.

[0200] According to an embodiment of the present invention, the PET-CT imaging agent is adapted for non-invasive in vivo imaging, quantification and / or monitoring of brown and / or beige adipose tissue (BAT) activity in human subjects.

[0201] Preferably, the PET-CT imaging agent is in the form of a biocompatible formulation. More preferably, the biocompatible formulation is an emulsion.

[0202] According to the present invention, the emulsion comprises a biocompatible emulsifier selected from the group comprising lecithin, polyoxyethylene sorbitan fatty acid esters, sucrose stearate, polyoxyethylene stearate, sucrose esters, sorbitan esters and / or mixtures thereof.

[0203] According to the embodiment, the amount of the biocompatible emulsifier in the emulsion is between 5 and 50% (w / w) of the total emulsion. Preferably, the amount of the biocompatible emulsifier in the emulsion is between 5 and 25% (w / w) of the total emulsion.

[0204] The amount of iodinated fatty acid of formula (I) and / or its esters and / or salts and / or mixtures should be at least 10% by weight of the emulsion and preferably at least 20% by weight, with a 30% content generally being preferred, although emulsions containing up to 40% contrast agent may be prepared in some cases. One or more emulsifying agents are preferably included in the composition.

[0205] Preferably, the emulsion is a microemulsion or nanoemulsion.

[0206] In other embodiments, the weight of the excipient may be, for example, between about 0.1% and about 75% of the total weight of the unit dose, or between about 2% and about 50% of the total weight of the unit dose, and any range derivable therein.

[0207] The active agent of the PET-CT contrast agent, and in particular the iodinated fatty acid having 16-18 carbon atoms of formula (I) and / or its ester and / or salt and / or mixture (dissolved in an organic solvent or neat), can be added to ion-free water or a buffer solution, preferably containing an emulsifier. The resulting mixture can be emulsified at a temperature above the melting point of the fatty acid using any method known to those skilled in the art to produce a finely dispersed oil-in-water emulsion. Agitation can be achieved by any known means, such as by using a high-shear agitator or ultrasonically. The aqueous phase can contain other excipients, such as preservatives (such as antimicrobials and / or antioxidants), stabilizers, texture modifiers, colorants, taste modifiers, pharmaceutically acceptable salts, and / or buffers. Suitable emulsions and methods for their preparation are described, for example, on pages 25-27 and Example 16 of WO 2019 / 030024 A1 and on pages 32-35 and Examples 1-10 of WO 2020 / 165349 A1. These patent documents are incorporated herein in their entirety.

[0208] Solid pharmaceutical forms are also contemplated for the PET-CT contrast agent, in which the active agent of the PET-CT contrast agent as described above is mixed with suitable excipients such as gelatin, polylactic acid, polylactic-polyglycolic acid, poloxamer, caprolactone, cellulose, sugars, sugar derivatives, salts, fatty acids and their derivatives.

[0209] Dosage and Administration of PET-CT Imaging Agents for Use in the Invention According to a preferred embodiment of the present invention, the PET-CT contrast agent is administered in a dose corresponding to between 0.004 and 0.5 mg of iodine per gram of body weight.

[0210] However, in certain embodiments, a unit dose of emulsion may contain, for example, a PET-CT imaging agent in a total amount of iodine corresponding to at least about 0.004 mg of iodine per gram of body weight. Similarly, in certain embodiments, a unit dose of emulsion may contain, for example, a PET-CT imaging agent in a total amount of iodine corresponding to no more than about 0.5 mg of iodine per gram of body weight.

[0211] In other non-limiting examples, the unit dose may comprise a PET-CT contrast agent containing iodine per administration in an amount of about 1 μg per kg of body weight (hereinafter "μg / kg body weight"), about 50 μg / kg body weight, about 100 μg / kg body weight, about 500 μg / kg body weight, about 1 mg / kg body weight, about 5 mg / kg body weight, about 10 mg / kg body weight, about 50 mg / kg body weight, about 100 mg / kg body weight, about 200 mg / kg body weight, about 300 mg / kg body weight, or the like. The amount may be about 350 mg / kg body weight, about 400 mg / kg body weight, about 450 mg / kg body weight, about 500 mg / kg body weight, about 600 mg / kg body weight, about 700 mg / kg body weight, about 800 mg / kg body weight, about 900 mg / kg body weight, about 1000 mg / kg body weight, about 2000 mg / kg body weight to about 5000 mg / kg body weight or more, and any range derivable therein. Non-limiting examples of ranges derivable from the numbers recited herein include ranges of about 350 mg / kg body weight to about 1000 mg / kg body weight, about 50 μg / kg body weight to about 500 mg / kg body weight, etc.

[0212] In any case, the dosage of the PET-CT contrast agent used will depend on the specific condition being diagnosed, the severity of the condition, individual patient parameters including age, physical condition, size and weight, duration of imaging, the nature of concomitant therapy (if any), and other similar factors that are within the knowledge and expertise of health professionals.These factors are known to those skilled in the art and can be addressed with minimal routine experimentation.Therefore, the optimal dosage can be determined by the practitioner who is diagnosing any particular patient.

[0213] PET Tracers for Use in the Present Invention A PET scan requires the administration of a radioactive tracer (also called a PET tracer or radiotracer) to be performed. The most commonly used radioactive tracers for cancer detection are: 18FDG (2-[fluorine-18]fluoro-2-deoxy-D-glucose), a radioactive glucose analogue, is injected intravenously prior to the PET scan, preferably as an isotonic, sterile, pyrogen-free, clear, colorless citrate buffer solution. The solution preferably contains, per mL, between 0.37 and 3.7 GBq (10.0 to 100 mCi) of 2-deoxy-2-[18F]fluoro-D-glucose at the end of synthesis, 4.5 mg of sodium chloride, and 7.2 mg of citrate ions. The pH of the solution is preferably between 5.0 and 7.5. The usual dose for adults is 100 mg / mL. 18 The FDG dose ranges from 185 to 370 MBq. Patients undergoing PET-CT scans: 18 Patients should fast for at least 4 hours before FDG administration. 18 During the intravenous injection and subsequent uptake phase of FDG, patients receive 18 To minimize FDG uptake, patients should remain silent, sitting or lying down. 18 To minimize FDG deposition, 18 Warming should begin 30–60 min before FDG injection and continue throughout the uptake period and the entire examination. 17 PET-CT scans are 18 It should be performed 55 to 75 minutes after FDG administration.

[0214] 11 C-acetate, 11 C-methionine, 11 C-choline, copper ( 64 Cu) dotatate, 18 F-EF5, 18 F-fluciclovine, 18 F-fluorocholine, 18 F-Fluoroethyl-L-tyrosine ( 18 F-FET), 18 F-fluoromisonidazole ( 18 F-FMISO), 18 F-fluorothymidine, 64 Cu-Cu-ETS2,68 Ga-DOTA-pseudopeptide, 68 Ga-DOTA-TATE, 68 Ga-PSMA, 68 Other radioactive tracers such as Ga-CXCR may also be used. The state of the art in such alternative PET tracers is described in F. Giammarile et al. 20 It has been reviewed by.

[0215] As noted above and below, according to some variations of the methods of the present invention: 18 It is possible to perform the methods of the present invention using other PET tracers in place of FDG. Thus, these variations of the methods of the present invention may rely on the PET tracers listed above and / or discussed in the review article by Gimmarile, cited above, which is incorporated herein in its entirety.

[0216] Not all alternative PET tracers are suitable for all types of cancer.However, those skilled in the art can rely on general knowledge, such as that reflected by the review article by Giammarile et al. mentioned above, to identify the suitable alternative PET tracer for the cancer type of interest.Unless otherwise indicated or unless the context indicates otherwise, 18 If another PET tracer is used instead of FDG, e.g., regarding its mode of administration, timing of administration, sequence of method steps, etc. 18 The additional guidance provided herein for the use of FDG can be applied in a similar manner to alternative PET tracers.

[0217] Special Embodiments The present application also relates to the following specific embodiments. It is contemplated that the information provided below for specific embodiments in this section may be combined with information provided in other sections of this text if and to the extent that such combination is technically reasonable, e.g., the respective combined information relates to the same type of method. However, it is also contemplated that the information provided below for specific embodiments in this section may be considered independently of the information provided in other sections of this text, as a distinct embodiment.

[0218] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of specific embodiments of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that specific embodiments of the present invention are not entitled to antedate such publications by virtue of prior invention. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0219] In case of conflict, the present specification, including definitions, will control.

[0220] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. As used herein, the following definitions are provided to facilitate understanding of particular embodiments of the present invention.

[0221] The term "comprise" is used generally in the sense of include, i.e. permitting the presence of one or more features or components.

[0222] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0223] As used herein, the terms "subject" or "patient" are well-recognized in the art and are used interchangeably herein to refer to mammals, including dogs, cats, rats, mice, monkeys, cows, horses, goats, sheep, pigs, camels, and most preferably humans. In some embodiments, the subject is a subject in need of diagnosis or a subject with a diagnosed disease or disorder. However, in other embodiments, the subject can be a healthy subject. The terms do not denote a particular age or sex. Thus, adult and neonatal subjects, whether male or female, are intended to be encompassed.

[0224] The term "formulation" or "pharmaceutical formulation" encompasses solid formulations such as tablets, enteric-coated tablets, controlled-release tablets, sustained-release tablets, capsules, and self-emulsifying pharmaceutical forms. It also encompasses liquid and semi-solid formulations such as solutions, suspensions, emulsions, topical preparations, suppositories, enemas, and parenteral formulations for injection and infusion.

[0225] The term "ethiolated oil" refers to an oil of natural origin that is converted by organic synthetic procedures to ethyl esters of iodinated fatty acids used as injectable radiopaque contrast agents, which are used to outline structures in radiological studies. Ethiolated oil is composed of iodine combined with the ethyl esters of fatty acids from poppy seed oil, primarily as ethyl monoiodostearate and ethyl diiodostearate. Although the exact structure is unknown, it is included within the definition of Formula I.

[0226] In chemistry, the term "geminal" as used herein refers to the relationship between two atoms or functional groups that are bonded to the same atom.

[0227] The related term "vicinal" refers to the relationship between two functional groups bonded to adjacent atoms. Currently, it is nearly impossible to synthesize stable iodinated fatty acids and / or esters thereof having iodine atoms bonded to adjacent carbon atoms (i.e., vicinal). Due to steric hindrance, these molecules are unstable and cannot be used for the purposes of specific embodiments of the present invention. However, in the future, those skilled in the art may be able to find a technical solution to this problem. Therefore, if stable iodinated fatty acids and / or esters thereof having iodine atoms in vicinal positions are provided, it is believed that these compounds would also be suitable for solving the technical problems of specific embodiments of the present invention.

[0228] As used herein, the term "alkyl" includes any long or short chain, straight or branched, saturated or unsaturated aliphatic hydrocarbon group. Unsaturated alkyl groups may be monovalent or polyunsaturated, and include both alkenyl and alkynyl groups. Such groups may contain up to 40 carbon atoms. However, alkyl groups containing up to 10, for example 8, more preferably up to 6, and especially preferably up to 4 carbon atoms are preferred.

[0229] The term "alkoxyl" refers to -O-alkyl. An example of an alkoxyl is C1-C6 alkoxyl, which represents a straight or branched alkyl chain having from 1 to 6 carbon atoms attached to an oxygen atom. Exemplary C1-C6 alkoxyl groups include methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, sec-butoxyl, t-butoxyl, pentoxyl, hexoxyl, and the like. C1-C6 alkoxyl includes C1-C4 alkoxyl within its definition.

[0230] The term "aryl," as used herein, refers to a carbocyclic or heterocyclic, aromatic, 5- to 14-membered monocyclic or polycyclic ring. Exemplary aryls include phenyl, naphthyl, anthryl, phenanthryl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindoli. These include benzoyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl.

[0231] In organic chemistry, a "saturated" compound is a chemical compound with a chain of carbon atoms linked together by single bonds. Alkanes are saturated hydrocarbons. An "unsaturated" compound is a chemical compound that contains a carbon-carbon double or triple bond, such as those found in alkenes or alkynes, respectively. Saturated and unsaturated compounds need not consist solely of a chain of carbon atoms. They can form linear, branched, or cyclic arrangements. They can also have functional groups. In this sense, fatty acids are classified as saturated or unsaturated. The amount of unsaturation in a fatty acid can be determined by finding its iodine value.

[0232] Unsaturated compounds are those that can undergo addition reactions. In carbon chains such as fatty acids, double or triple bonds cause twists in the chain. These twists have macrostructural implications. Unsaturated lipids tend to be liquids rather than solids at room temperature because the twists in the chain prevent the molecules from packing tightly together to form a solid, and these lipids are called oils.

[0233] The term "polyhydroxy" or polyhydroxy refers to a chemical compound that contains two or more hydroxyl groups per molecule.

[0234] Positron emission tomography-computed tomography (PET-CT) is a nuclear medicine technique that combines a positron emission tomography (PET) scanner and an X-ray computed tomography (CT) scanner in a single gantry to acquire sequential images from both devices in the same session. The images are combined into a single overlapping (co-registered) image. Thus, functional images acquired by PET, depicting the spatial distribution of metabolic or biochemical activity in the body, can be more accurately aligned or correlated with anatomical images acquired by CT scanning. Two- and three-dimensional image reconstructions can be rendered as a function of common software and control systems.

[0235] PET scans use a radioactive tracer, usually 18PET scans require the administration of FDG. The tracer is injected before the PET scan. CT does not require the use of contrast agents for anatomical contouring. However, a contrast agent may be administered to the patient before the CT scan. This is useful for highlighting structures such as blood vessels that would otherwise be difficult to distinguish from their surroundings. The use of contrast agents can also help obtain functional information about tissues. CT contrast agents are usually administered intravenously. Intra-arterial or intrathecal injections can also be used in some indications. Water-soluble CT contrast agents are used to visualize vascular structures and / or organs. They can also be used to diagnose tumors due to their different uptake and efflux kinetics from surrounding tissues. The CT contrast agent may be any molecule intended for vascular imaging, including, but not limited to, iomeprol, ioversol, iopromide, iohexol, iodixanol, diatrizoate meglumine, metrizoate, iothalamate meglumine, iodipamide meglumine, iopamidol, ioxilan, ioxaglate, and ioversol.

[0236] The objectives of particular embodiments of the present invention are to 18 1. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue by PET-CT imaging in a human cancer patient who has received prior administration of an FDG PET tracer, comprising: a) administering to said human cancer patient a compound of general formula I:

[0237] [ka] (wherein n=14 to 16, R1 is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is H, unsaturated or saturated, linear or branched alkyl, alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl or alkylcarbonyloxyalkyl) administering an oral CT contrast agent comprising an iodinated fatty acid and / or an ester and / or a salt and / or a mixture thereof according to The administration of the oral CT contrast agent 18 performed at least 3 hours prior to administration of the FDG PET tracer; b) performing a PET-CT scan on the human cancer patient; c) determining whether the primary tumor and / or metastasis is distinct from brown and / or beige tissue in the human cancer patient; 18 comparing both the PET and CT scans to assess co-localization of positive contrast enhancement of FDG and said CT contrast agent; The object of the present invention is to provide a method comprising:

[0238] The CT contrast agent is adapted for oral (ie, peroral) route.

[0239] The PET-CT scan can be prescribed for tumor diagnosis or staging, for evaluating the efficacy of therapy, for evaluating the progression of cancer, or for any reason that may be relevant to the treating oncologist or physician.If both the PET tracer and the CT contrast agent are superimposed (located at the same position on the PET and CT scans), it means that the PET tracer is taken up by brown adipose tissue.On the other hand, if the PET tracer does not overlap with the CT contrast agent described in the specific embodiment of the present invention, it can exclude the PET tracer uptake by brown or beige adipose tissue.

[0240] In a preferred embodiment of a particular embodiment, the overlay of the PET and CT scans is based on a sagittal view, which is preferred because it avoids time-consuming evaluation of axial slices of both the PET and CT scans by a radiologist and / or nuclear medicine physician.

[0241] In another embodiment of a particular embodiment of the present invention, the overlay and evaluation of scan overlap of the PET tracer and the CT contrast agent is performed by software or a plug-in or add-in or add-on to existing software.

[0242] Preferably, the software analysis is performed by machine learning such as ANN, RNN, DL or CNN techniques.

[0243] "Machine learning" is the science of getting computers to learn and behave like humans, autonomously improving their learning over time by feeding them data and information in the form of observations and real-world interactions. A fundamental goal of machine learning algorithms is to generalize beyond the training examples, i.e., to successfully interpret data that they have never "seen" before.

[0244] "Deep learning," as used in particular embodiments of the present invention, refers to a collection of algorithms used in machine learning that are used to model high-level abstractions in data through the use of model architectures composed of multiple nonlinear transformations. It is part of a broad family of methods used in machine learning that are based on learned representations of data. Deep learning is a specific approach used to build and train neural networks, which are considered highly promising decision nodes. An algorithm is considered deep if the input data passes through a series of nonlinearities or nonlinear transformations before becoming the output. In contrast, most modern machine learning algorithms are considered "shallow" because the input can only go through a few levels of subroutine calls.

[0245] Deep learning eliminates the manual identification of features in data and instead relies on whatever training process must discover useful patterns in the input examples. This makes neural networks easier and faster to train and can produce better results when applied to measuring bgl.

[0246] Within deep learning, this particular embodiment uses many deep learning methods, including but not limited to: recurrent neural networks and convolutional neural networks.

[0247] A "recurrent neural network" or "RNN" is a class of artificial neural networks in which connections between nodes form a directed graph along a sequence. This allows them to exhibit temporally dynamic behavior over a time series. The use of recurrent neural networks as a methodology in obtaining BGL is illustrated in FIG. 17. They are particularly powerful in use cases where context is critical for predicting outcomes, and they differ from other types of artificial neural networks because they use feedback loops to process sequences of data that convey a final output, which can also be a sequence of data. These feedback loops persist information.

[0248] In some cases, artificial neural networks process information unidirectionally, from input to output. These "feedforward" neural networks include the convolutional neural networks that underpin image recognition systems. RNNs, on the other hand, are layered and can process information bidirectionally.

[0249] A "convolutional neural network" (CNN) is a type of artificial neural network used primarily in image recognition and processing that is specifically designed to process pixel data. CNNs are powerful image processing networks that use deep learning to perform both generative and descriptive tasks, often used in machine vision, including image and video recognition, as well as recommendation systems and natural language processing. These neural networks have their "neurons" arranged in such a way that they cover the entire field of view while avoiding the fragmented image processing problem of traditional neural networks.

[0250] The layers of a CNN consist of an input layer, an output layer, and a hidden layer that includes multiple convolutional, pooling, fully connected, and normalization layers. The removal of limitations and increased efficiency for image processing results in a much more effective and simpler system than training limited to image processing and natural language processing.

[0251] Preferably, the R2 group may be mono- or polysubstituted. Suitable R2 groups include alkyl substituents, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropylmethyl, pentyl, isopentyl, hexyl, isohexyl, heptly, isoheptyl, octyl, isooctyl, 2-propenyl, allyl, crotyl, 1-butenyl, 2-butenyl, butadienyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and propagyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl; aryl substituents, such as fluoromethyl, ... The substituents may include, but are not limited to, phenyl, naphthyl, anisyl, toluyl, xylenyl, aryloxy, aralkyl, aralkyloxy, heteroaryl groups (pyrimidine, morpholine, piperazine, piperidine, thiophene), 1-cyclohexylpropyl, or the set of haloalkyl substituents, by way of example, fluoromethyl, 1-fluoroethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl and pentafluoroethyl, chlorodimethyl, chloromethyl, 2-chloroethyl, 2,4-dichlorophenyl, 1,1,2,2-tetrachloroethyl, 1-chlorobutyl, and 4-chlorobenzyl.

[0252] This can include substituted alkyl groups such as 9-fluorenylmethyl, methoxyethoxymethyl, tetrahydropyranyl, pivaloyloxymethyl, phenylacetoxymethyl, phenacyl and substituted phenacyls such as p-bromophenacyl, p-methoxyphenacyl, and also t-butyl, 3-methyl-3-pentyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, cinnamyl, oxazole and 2-alkyl-1,3-oxazoline.

[0253] This may include alkylaryl, such as benzyl, substituted benzyl, for example, triphenylmethyl, p-methoxybenzyl, 4-picolyl, diphenylmethylphenylethyl, substituted phenylethyl, but also alkoxyalkyl, for example, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, isobutoxyethyl, hydroxyalkoxyalkyl, for example, hydroxymethoxymethyl, 2-hydroxyethoxymethyl, 3-hydroxypropoxymethyl, 4-hydroxybutoxymethyl, hydroxymethoxyethyl, hydroxymethoxypropylhydroxymethoxybutyl, hydroxymethoxypentyl, hydroxymethoxyhexyl, polyhydroxyalkyl and hydroxypolyalkyleneoxyalkyl, and also carbonyloxyalkyl, for example, acetoyloxymethyl, propanoyloxymethyl, butanoyloxymethyl, pentanoyloxymethyl, hexanoyloxymethyl, pivaloyloxymethyl, and similar groups.

[0254] Iodinated fatty acids having 16 to 18 carbon atoms and / or esters and / or salts and / or mixtures thereof according to general formula I include the following sub-formulae A, B and C, depending on the starting materials used:

[0255] [ka] In the formula, n is an integer of 1 to 6, x and y are carbon atoms, x = 0 to 15 and y = 0 to 15, and x + y ≦ 15, with the proviso that the total number of carbon atoms in formula A, B, or C is 20 or less, respectively, R1 is H or I, with the proviso that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal, and the R2 group may be mono- or polysubstituted.

[0256] Thus, suitable R groups include, for example, unsubstituted alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, and the like, as well as substituted alkyl groups, such as 9-fluorenylmethyl, methoxyethoxymethyl, tetrahydropyranyl, pivaloyloxymethyl, phenylacetoxymethyl, phenacyl, and substituted phenacyl, such as p-bromophenacyl, p-methoxyphenacyl, and also t-butyl, 3-methyl-3-pentyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1yl, cinnamyl, oxazole, 2-alkyl-1,3-oxazoline, and the like. This includes alkylaryl, such as benzyl, substituted benzyl, for example, triphenylmethyl, p-methoxybenzyl, 4-picolyl, diphenylmethylphenylethyl, substituted phenylethyl, but also alkoxyalkyl, such as methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, isobutoxyethyl, hydroxyalkoxyalkyl, such as hydroxymethoxymethyl, 2-hydroxyethoxymethyl, 3-hydroxypropoxymethyl, 4-hydroxybutoxymethyl, hydroxymethoxyethyl, hydroxymethoxypropylhydroxymethoxybutyl, hydroxymethoxypentyl, hydroxymethoxyhexyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl, and also carbonyloxyalkyl, such as acetoyloxymethyl, propanoyloxymethyl, butanoyloxymethyl, pentanoyloxymethyl, hexanoyloxymethyl, pivaloyloxymethyl, and similar groups.

[0257] According to particular embodiments, iodinated fatty acids having 16 to 18 carbon atoms and / or their esters and / or mixtures may exist as isomeric mixtures or single isomers. Unless specified, both isomeric forms are intended. When a particular embodiment of a compound contains one chiral center, the iodinated compound may be provided as a single isomer (R or S) or as a mixture of isomers, e.g., a racemic mixture. When a particular embodiment of an iodinated compound contains more than one chiral center, the iodinated compound may be provided as an enantiomerically pure diastereoisomer or as a mixture of diastereoisomers.

[0258] According to certain specific embodiments, it is also envisaged that the oral contrast agent comprises an iodinated fatty acid and / or ester thereof having 4 to 24 carbon atoms, which may be used in a mixture comprising several or at least two iodinated fatty acids with different carbon chains of 4 to 24 carbon atoms. In a preferred specific embodiment, the contrast agent comprises an iodinated fatty acid according to general formula I, preferably having 10 to 20 carbon atoms, more preferably 16 to 18 carbon atoms. In an even more preferred embodiment, the iodinated fatty acid is iodinated linolenic acid.

[0259] Preferably, the iodiodinated fatty acid is periodated.

[0260] According to a preferred embodiment, iodinated fatty acids containing 12 to 20 carbon atoms, preferably 14 to 18, even more preferably 16 to 18 carbon atoms and / or esters and / or salts and / or mixtures thereof may be used according to a particular embodiment of the present invention.

[0261] In another embodiment, the iodinated fatty acids and / or esters and / or mixtures thereof having 16 to 18 carbon atoms according to particular embodiments of the present invention have at least one asymmetric center. As a result of this asymmetric center, the iodinated compounds of particular embodiments of the present invention can occur in any of the possible stereoisomeric forms and can be used in mixtures of stereoisomers, can be optically active or racemic, or can be used singly as essentially pure stereoisomers, i.e., at least 95% pure. All asymmetric forms, individual stereoisomers, and combinations thereof are within the scope of particular embodiments of the present invention.

[0262] According to yet another particular embodiment, the contrast agent consists of iodinated fatty acids and / or esters thereof having 16-18 carbon atoms, which may be used in mixtures containing several or at least two iodinated fatty acids having 16-18 carbon atoms. Preferably, the contrast agent is a biocompatible emulsion of iodinated fatty acids having 16-18 carbon atoms according to general formula I:

[0263] According to another embodiment, the biocompatible formulation is a formulation of ethiodized oil.

[0264] According to a further particular embodiment, the biocompatible formulation of the contrast agent is an emulsion. Preferably, the emulsion is a nanoemulsion.

[0265] According to yet another particular embodiment, oral contrast agents composed of biocompatible emulsions of iodinated fatty acids having 16 to 18 carbon atoms and / or their esters can be used in mixtures containing several or at least two iodinated fatty acids.

[0266] In a preferred particular embodiment, the imaging agent is comprised of a biocompatible emulsion of iodinated fatty acids having 16 to 18 carbon atoms according to general formula I.

[0267] In a more preferred embodiment, the iodinated fatty acid is iodinated linolenic acid.

[0268] Preferably, the iodinated fatty acid is periodated.

[0269] According to yet another particular embodiment, the contrast agent is composed of a biocompatible nanoemulsion of iodinated fatty acids and / or their esters having 16-18 carbon atoms, which may be used in a mixture containing several or at least two iodinated fatty acids with different carbon chains of 16-18 carbon atoms. Preferably, the contrast agent is a biocompatible emulsion of iodinated fatty acids having 16-18 carbon atoms according to general formula I:

[0270] Solid pharmaceutical forms comprising a computed tomography contrast agent mixed with suitable excipients such as gelatin, polylactic acid, polylactic-polyglycolic acid, poloxamer, caprolactone, cellulose, sugars, sugar derivatives, salts, fatty acids and their derivatives are also contemplated.

[0271] 18 Poorer outcomes are usually observed in cancer patients with highly active brown adipose tissue, characterized by FDG uptake 8 In these patients, the more metabolically active brown adipose tissue ( 18 Higher BAT volume (characterized by FDG uptake) was associated with a more active neoplastic state. Higher BAT volume was associated with an increased likelihood of tumor recurrence and / or tumor-related mortality. 9 This may be related not only to tumor severity (inflammatory and tumor factors that promote brown adipose tissue activation and white adipose tissue browning) but also to the incidence of cachexia, a fatal body-wasting syndrome associated with cancer and chronic disease.

[0272] in BAT that is visible on PET and / or CT scans 18 FDG and / or contrast agent uptake is a result of BAT volume and / or activity, respectively.

[0273] According to certain particular embodiments, the oral imaging agent is adapted for non-invasive in vivo imaging, quantification and / or monitoring of brown and / or beige adipose tissue (BAT) activity in said human cancer patients.

[0274] Preferably, the oral contrast agent is in the form of a biocompatible formulation. More preferably, the biocompatible formulation is an emulsion.

[0275] According to a particular embodiment, the emulsion comprises a biocompatible emulsifier selected from the group comprising lecithin, polyoxyethylene sorbitan fatty acid esters, sucrose stearate, polyoxyethylene stearate, sucrose esters, sorbitan esters and / or mixtures thereof.

[0276] According to the embodiment, the amount of the biocompatible emulsifier in the emulsion is between 5 and 50% (w / w) of the total emulsion. Preferably, the amount of the biocompatible emulsifier in the emulsion is between 5 and 25% (w / w) of the total emulsion.

[0277] According to another particular embodiment, the oral CT contrast agent is administered in a dose corresponding to between 0.004 and 0.5 mg of iodine per gram of body weight.

[0278] The cancer diagnosed by the method is preferably selected from the group comprising or consisting of lung, colorectal, breast, gynecological, head and neck, esophageal, gastric, biliary tract, follicular and medullary thyroid, and pancreatic cancer, leukemia, melanoma, lymphoma, multiple myeloma, sarcoma, primary brain tumor, pheochromocytoma, lipoma, myolipoma, or hibernation adenoma.

[0279] According to another embodiment, the method of particular embodiments of the present invention is adapted for the detection or diagnosis of cancer and / or staging and / or restaging of cancer in said human cancer patient and / or for assessing the treatment success of said cancer.

[0280] In a preferred embodiment, the methods of particular embodiments of the present invention are adapted for use in human patients under the age of 18.

[0281] As mentioned earlier, in brown adipose tissue 18 FDG uptake is 18 It is observed in approximately 5% of patients undergoing FDG PET-CT scans. Information about the volume of brown adipose tissue and its level of activation would provide cancer patients' caregivers with valuable information regarding cancer prognosis. This can be achieved by using the CT contrast agents described in particular embodiments of the present invention during planned diagnostic and / or staging PET-CT scans prescribed by an oncologist or another physician.

[0282] In certain embodiments, administration of a CT contrast agent prior to a PET-CT scan is adapted for non-invasive in vivo imaging, quantification and / or monitoring of brown and / or beige adipose tissue (BAT) activity in a subject, allowing for more accurate prognosis of the cancer being treated and resulting in more tailored treatment. a) administering a CT contrast agent (as described above) comprising a biocompatible formulation of an iodinated fatty acid having 16 to 18 carbon atoms and / or its esters and / or salts and / or mixtures according to general formula I; b) PET tracer ( 18 FDG) and c) performing a PET-CT scan; d) comparing the PET-CT scan with that of a healthy individual; Complies with.

[0283] The acquired scans can be used separately or in combination to assess the presence of tumors and / or metastases (PET) and the degree of uptake of the CT contrast agent in brown adipose tissue (indicating the activity and / or surface area and / or volume of brown adipose tissue).

[0284] Both parameters taken separately or together are 18 This allows for more accurate cancer prognosis than PET-CT using FDG tracer alone. The addition of this specific CT contrast agent allows for more accurate prognosis of cancer progression and outcome, depending on the degree of CT contrast uptake in brown adipose tissue and the volume of brown adipose tissue. For most malignancies, increased uptake in brown adipose tissue indicates a poorer cancer prognosis.

[0285] The CT contrast agent is adapted for oral (ie, peroral) route.

[0286] The PET-CT scan may be prescribed for tumor detection, diagnosis or staging, to assess the efficacy of therapy, to assess the progression of cancer, or for any reason deemed relevant to the treating oncologist or physician.

[0287] According to one embodiment, the administration of the oral CT contrast agent occurs the day before the planned PET-CT scan. 18 at least 10 hours prior to administration of the FDG PET tracer, more preferably 18 It is performed at least 6 hours, 4 hours, and even more preferably at least 3 hours before administration of the FDG PET tracer.

[0288] According to a preferred embodiment, the oral CT contrast agent of the method according to the particular embodiment is administered in a dose corresponding to between 0.004 and 0.5 mg of iodine per gram of body weight.

[0289] However, in certain embodiments, the nanoemulsion may contain, for example, at least about 0.004 mg of iodine per gram of body weight of the oral CT contrast agent of particular embodiments. In other embodiments, the excipient may comprise, for example, between about 0.1% and about 75% of the weight of the unit, or between about 2% and about 30%, and any range derivable therein.

[0290] In other non-limiting examples, dosages may include about 1 μg / kg / body weight, about 100 μg / kg / body weight, about 500 μg / kg / body weight, about 1 mg / kg / body weight, about 5 mg / kg / body weight, about 10 mg / kg / body weight, about 50 mg / kg / body weight, about 100 mg / kg / body weight, about 200 mg / kg / body weight, about 300 mg / kg / body weight, about 350 mg / kg / body weight, about 400 mg / kg / body weight, about 450 mg / kg / body weight, about 500 mg / kg / body weight, about 600 mg / kg / body weight, about 700 mg / kg / body weight, about 800 mg / kg / body weight, about 900 mg / kg / body weight, about 1000 mg / kg / body weight, about 2000 mg / kg / body weight to about 5000 mg / kg / body weight or more per administration, and any range derivable therein. Non-limiting examples of ranges that can be derived from the numbers given herein include ranges of about 350 mg / kg / body weight to about 1000 mg / kg / body weight, about 50 μg / kg / body weight to about 500 mg / kg / body weight, etc.

[0291] In any case, the dosage of the oral CT contrast agent used will depend on the specific condition being diagnosed, the severity of the condition, individual patient parameters including age, physical condition, size and weight, duration of imaging, the nature of concomitant therapy (if any), and other similar factors that are within the knowledge and expertise of the health professional.These factors are known to those skilled in the art and can be addressed with minimal routine experimentation.Therefore, the optimal dosage can be determined by the practitioner who is diagnosing any particular patient.

[0292] The primary substrate of brown or beige adipocytes is fatty acids rather than glucose. 18 While other imaging methods for brown or beige adipose tissue, such as FDG-PET, require activation of brown adipose tissue, Applicants have observed that brown and beige adipose tissue can be imaged without prior activation of these tissues by use of the oral CT contrast agents described in particular embodiments of the present invention. This is due to the lack of activation of off-target tissue (metabolically active tissue, including non-malignant brown adipose tissue). 18 FDG uptake should be avoided whenever possible, combined 18This is particularly advantageous in the case of FDG PET-CT scans.

[0293] Preparation: It is understood that any suitable method for preparing the iodinated fatty acids having 16 to 18 carbon atoms of formula (I) and / or esters thereof that is known to a person skilled in the art may be encompassed by the scope of specific embodiments of the present invention.

[0294] emulsion: Formulation optimization was performed by experimental design. Several parameters were evaluated, including the active CT ingredient, the type and amount of excipients, their compatibility, and the preparation method. The selection of the optimal formulation was based on physicochemical properties, stability, and biocompatibility.

[0295] Emulsions were prepared by dissolving iodinated fatty acids in water, which would improve their intestinal absorption. The emulsion formulation was improved to achieve the fastest and most complete absorption of the contrast agent. The aim of this final step was to achieve the highest enhancement at the lowest possible dose. The contrast agent was then tested under different conditions of brown lipid activation to demonstrate its potential in assessing brown lipid metabolism.

[0296] The following features should be realized: Minimal amount of emulsifier · Low viscosity Biocompatible (non-toxic and non-irritating at required doses) Long-term stability of emulsions when stored at 4°C for long periods or at 25°C for shorter periods Material and processing cost effectiveness

[0297] Lecithin, polyoxyethylene sorbitan fatty acid esters, sucrose stearate, polyoxyethylene stearate, sucrose esters and sorbitan ester surfactants are preferred excipients used to prepare emulsions because they have long documented safe use in cosmetics, foodstuffs and pharmaceutical formulations (oral, parenteral and topical).

[0298] The fatty acid or its derivative (dissolved in an organic solvent or undiluted) can be added to ion-free water or a buffer solution, preferably containing an emulsifier, with vigorous stirring at a temperature above the melting point of the fatty acid to produce a finely dispersed oil-in-water emulsion. Stirring can be achieved by any known means, such as by using a high-shear stirrer or ultrasonically. The aqueous phase can contain other excipients, such as preservatives (such as antimicrobials and / or antioxidants), stabilizers, texture modifiers, colorants, taste modifiers, pharmaceutically acceptable salts, and / or buffers.

[0299] The amount of iodinated fatty acid or derivative thereof should be at least 10% by weight of the concentrated emulsion, preferably at least 20% by weight, with a 30% content generally being preferred, although emulsions as high as 40% may be prepared in some cases. A small amount of emulsifier is preferably included in the composition.

[0300] When an emulsifier is used, the viscosity of the emulsion will vary with the water / oil phase ratio, and will usually reach a maximum value as the water / fatty acid ratio increases.To obtain a fine emulsion, it is preferable to stir for a certain period of time at a water / fatty acid ratio close to or slightly in excess of that required for maximum viscosity, and then add additional ion-free water while continuing to stir to obtain the desired iodinated fatty acid concentration.The emulsion is then cooled to room temperature.

[0301] Another object of particular embodiments of the present invention is to 18 1. A prognostic method for cancer assessment by assessing the amount of activated brown and / or beige tissue by PET-CT imaging in human cancer patients who have received prior administration of an FDG PET tracer, comprising: a) administering to the cancer patient a compound of formula I:

[0302] [ka] (wherein n=14 to 16, R1 is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is H, unsaturated or saturated, linear or branched alkyl, alkyl, alkoxyalkyl, alkylcarbonyloxymethyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl) administering an oral CT contrast agent comprising an iodinated fatty acid and / or an ester and / or a salt and / or a mixture thereof according to The administration of the oral CT contrast agent 18 performed at least 3 hours prior to administration of the FDG PET tracer; b) performing a PET-CT scan on the human cancer patient; c) assessing the progression of cancer by PET scan and the prognosis of cancer by CT scan; Including, The present invention provides a method in which uptake of an oral CT contrast agent by brown adipose tissue as observed on CT scans correlates with the prognosis of cancer patients, with higher uptake resulting in a poor prognosis compared to healthy individuals, whereas lower uptake results in a better cancer outcome for said human cancer patients.

[0303] According to preferred embodiments, the cancer diagnosed is selected from the group comprising or consisting of pheochromocytoma, lipoma, myolipoma, hibernation adenoma, lung, colorectal, breast, gynecological, head and neck, esophageal, gastric, biliary tract, follicular and medullary thyroid, and pancreatic cancer, leukemia, melanoma, lymphoma, multiple myeloma, sarcoma, and primary brain tumors.

[0304] According to a particular embodiment, the oral CT contrast agent is a biocompatible emulsion of iodinated fatty acids, preferably having 16 to 18 carbon atoms, according to general formula I:

[0305] 1. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue in a human cancer patient by PET-CT imaging, comprising: a) administering to said human cancer patient a compound of general formula I:

[0306] [ka] (wherein n=14 to 16, R1 is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is H, unsaturated or saturated, linear or branched alkyl, alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl or alkylcarbonyloxyalkyl) administering an oral CT contrast agent comprising an iodinated fatty acid and / or an ester and / or a salt and / or a mixture thereof according to The administration of the oral CT contrast agent 18 performed at least 3 hours prior to administration of the FDG PET tracer; b) By intravenous injection 18 administering FDG to the human cancer patient; c) for the human cancer patient 18 performing an FDG PET-CT scan; d) detecting primary tumors and / or metastases from brown and / or beige tissue in said human cancer patient. 18 comparing both the PET and CT scans to assess co-localization of positive contrast enhancement of FDG and said CT contrast agent; are also encompassed by particular embodiments of the present invention.

[0307] A still further object of particular embodiments is to provide compounds of general formula I:

[0308] [ka] (wherein n=14 to 16, R1 is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is H, unsaturated or saturated, linear or branched alkyl, alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl or alkylcarbonyloxyalkyl) of an oral CT contrast agent comprising an iodinated fatty acid and / or an ester and / or a salt and / or a mixture thereof according to 18 1. Use in a PET-CT imaging method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue in a human cancer patient who has received prior administration of an FDG PET tracer, comprising: a) For the human cancer patient 18 performing an FDG PET-CT scan; b) determining whether the primary tumor and / or metastasis is brown and / or beige in said human cancer patient; 18 comparing both the PET and CT scans to assess co-localization of positive contrast enhancement of FDG and said CT contrast agent; Including, However, the CT oral contrast agent for use is 18 administered at least 3 hours before administration of the FDG PET tracer, In the method, use.

[0309] Another object of particular embodiments of the present invention is to provide a prognostic method for detecting and / or assessing cancer in a patient by adding further information from one single CT or dual-energy CT (DECT) scan, comprising the combined administration of an oral CT contrast agent (Formula I) described herein and a water-soluble CT contrast agent administered by parenteral route to a patient suspected of developing cancer. CT or DECT is performed as follows: 1) Oral administration of a CT contrast agent according to Formula I; 2) parenteral administration of water-soluble radiocontrast agents; 3) Performing a CT or DECT scan on said patient.

[0310] Brown adipose tissue uptake of oral CT contrast agents correlates with the prognosis of cancer patients, depending on the cancer type. For most cancers, higher-than-normal uptake indicates a poor prognosis and warrants additional medical attention.

[0311] Both objectives of this particular embodiment (detection of malignant tissue and assessment of cancer prognosis) can be performed simultaneously in the same CT or DECT scan.

[0312] Dual-energy CT (DECT), also known as spectral CT, is a computed tomography technique that uses two separate x-ray photon energy spectra to allow for the matching of materials with different attenuation characteristics at different energies. While conventional single-energy CT produces a single image set, dual-energy data (attenuation values ​​at two energy spectra) can be used to reconstruct multiple image types.

[0313] Water soluble CT radiological contrast agents that may be used are selected from the following non-exhaustive list: 1. Hyperosmolar contrast media - diatrizoate sodium / meglumine (Gastrografin, MD-Gastroview, Cystografin), metrizoate (Isoparque), and iothalamate sodium / meglumine (Conray, Cysto-Conray) 2. Low osmolarity contrast media - Iopamidol (Isobue), Iohexol (Omnipaque), Iomeprol (Iomeron), Iopromide (Ultravist), Ioversol (Optiray), Ioxilan (Oxirane), Iodixanol (Visipaque), Ioxaglate (Hexabrix), Iodixanol (Visipaque) and others.

[0314] Therefore, it is an object of particular embodiments of the present invention to combine the administration of an oral CT contrast agent as described herein with the administration of a parenteral water-soluble CT radiocontrast agent for diagnosing and / or staging tumors, and / or for assessing the efficacy of treatment, and / or for assessing the progression of cancer, and / or for assessing the prognosis of cancer, and / or for any reason deemed relevant to the treating oncologist or physician. The imaging modality is CT or DECT. This imaging modality can be used in combination with the imaging modality described above. 18 It can also be combined with FDG PET scans. The addition of oral CT contrast agents described in particular embodiments of the present invention can help predict the occurrence of cachexia in patients, which, as mentioned above, can also serve as a prognosis for cancer progression.

[0315] Another object of particular embodiments of the present invention is to 18 1. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue by PET-DECT imaging in a human cancer patient who has received prior administration of an FDG PET tracer, comprising: a) administering to said human cancer patient a compound of general formula I:

[0316] [ka] (wherein n=14 to 16, R1 is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is H, unsaturated or saturated, linear or branched alkyl, alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl or alkylcarbonyloxyalkyl) administering an oral CT contrast agent comprising an iodinated fatty acid and / or an ester and / or a salt and / or a mixture thereof according to The administration of the oral CT contrast agent 18performed at least 3 hours prior to administration of the FDG PET tracer; b) for the human cancer patient 18 performing an FDG PET-DECT scan; c) determining whether the primary tumor and / or metastasis is distinct from brown and / or beige tissue in the human cancer patient; 18 comparing both the PET and DECT scans to assess co-localization of positive contrast enhancement of FDG and the oral CT contrast agent; The object of the present invention is to provide a method comprising:

[0317] Those skilled in the art will recognize that the specific embodiments described herein are susceptible to variations and modifications other than those specifically described. It is understood that the specific embodiments include all such variations and modifications without departing from their spirit or essential characteristics. The specific embodiments also include all of the steps, features, compositions, and compounds referred to or indicated herein, individually or collectively, and any and all combinations or any two or more of said steps or features. Accordingly, the present disclosure, in all its illustrative and not restrictive aspects, should be considered to be within the scope of the specific embodiments indicated by the appended claims, and all changes that come within the meaning and range of equivalence are intended to be embraced therein.

[0318] The foregoing description will be more fully understood with reference to the following examples. However, such examples are illustrative of methods of practicing particular embodiments of the invention and are not intended to limit the scope of the particular embodiments.

[0319] Particular embodiments of the present invention further relate to the following numbered items:

[0320] 1. 181. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue by PET-CT imaging in a human cancer patient who has received prior administration of an FDG PET tracer, comprising: a) administering to said human cancer patient a compound of general formula I:

[0321] [ka] (wherein n=14 to 16, R1 is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is H, unsaturated or saturated, linear or branched alkyl, alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl or alkylcarbonyloxyalkyl) administering an oral CT contrast agent comprising an iodinated fatty acid and / or an ester and / or a salt and / or a mixture thereof according to The administration of the oral CT contrast agent 18 performed at least 3 hours prior to administration of the FDG PET tracer; b) for the human cancer patient 18 performing an FDG PET-CT scan; c) determining whether or not a primary tumor and / or metastasis is present in said human cancer patient, so as to distinguish said primary tumor and / or metastasis from brown and / or beige adipose tissue; 18 comparing both the PET and CT scans to assess co-localization of positive contrast enhancement of FDG and said CT contrast agent; A method comprising:

[0322] 2. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue according to item 1, wherein the oral CT contrast agent is adapted for non-invasive in vivo imaging, quantification and / or monitoring of the activity of brown and / or beige adipose tissue (BAT) in said human cancer patient.

[0323] 3. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue according to either item 1 or 2, wherein the oral CT contrast agent is in the form of a biocompatible formulation.

[0324] 4. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue according to any of items 1 to 3, wherein the biocompatible preparation is an emulsion.

[0325] 5. The method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue according to item 4, wherein the emulsion comprises a biocompatible emulsifier selected from the group comprising lecithin, polyoxyethylene sorbitan fatty acid esters, sucrose stearate, polyoxyethylene stearate, sucrose esters, sorbitan esters and / or mixtures thereof.

[0326] 6. The method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue according to item 5, wherein the amount of the biocompatible emulsifier in the emulsion is between 3 and 50% (w / w) of the total emulsion.

[0327] 7. The method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue according to item 5, wherein the amount of the biocompatible emulsifier in the emulsion is between 5 and 25% (w / w) of the total emulsion.

[0328] 8. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue according to any of items 1 to 7, wherein an oral CT contrast agent is administered at a dose corresponding to between 0.004 and 0.5 mg of iodine per gram of body weight.

[0329] 9. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue according to any of items 1 to 7, wherein an oral CT contrast agent is administered at a dose corresponding to between 0.02 and 0.2 mg of iodine per gram of body weight.

[0330] 10. The method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue according to any of items 1 to 9, wherein the cancer is selected from the group consisting of lung, colorectal, breast, gynecological, head and neck, esophageal, gastric, biliary tract, follicular and medullary thyroid, and pancreatic cancer, leukemia, melanoma, lymphoma, multiple myeloma, sarcoma, pheochromocytoma, and primary brain tumors.

[0331] 11. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue according to any of items 1 to 10, adapted for use in human subjects under the age of 18.

[0332] 12. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue according to any of items 1 to 11, adapted for cancer detection and / or cancer staging and / or cancer restaging in said human cancer patient, and / or for assessing the success of a treatment of said cancer.

[0333] 13. 18 1. A prognostic method for cancer assessment by assessing brown and / or beige adipose tissue mass and / or volume and / or activity by PET-CT imaging in human cancer patients who have received prior administration of an FDG PET tracer, comprising: a) administering to the cancer patient a compound of formula I:

[0334] [ka] (wherein n=14 to 16, R1 is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is H, unsaturated or saturated, linear or branched alkyl, alkyl, alkoxyalkyl, alkylcarbonyloxymethyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl) administering an oral CT contrast agent comprising an iodinated fatty acid and / or an ester and / or a salt and / or a mixture thereof according to The administration of the oral CT contrast agent 18 performed at least 3 hours prior to administration of the FDG PET tracer; b) for the human cancer patient 18 performing an FDG PET-CT scan; c) assessing the progression of cancer by PET scan and the prognosis of cancer by CT scan; Including, A method characterized in that uptake of an oral CT contrast agent by brown adipose tissue observed on CT scans correlates with the prognosis of cancer patients, with higher uptake resulting in a poor prognosis compared to healthy individuals, while lower uptake results in a better cancer outcome for said human cancer patients.

[0335] 14. A prognostic method for cancer assessment by assessing the amount of active brown and / or beige adipose tissue according to item 12, wherein the cancer is selected from the group consisting of pheochromocytoma, lung, colorectal, breast, gynecological, head and neck, esophageal, gastric, biliary tract, follicular and medullary thyroid, and pancreatic cancer, leukemia, melanoma, lymphoma, multiple myeloma, sarcoma, and primary brain tumors.

[0336] 15. A prognostic method for cancer assessment according to any of items 12 to 14, wherein the oral CT contrast agent is a biocompatible emulsion of iodinated fatty acids having 16 to 18 carbon atoms according to general formula I:

[0337] 16. A method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue in human cancer patients by PET-CT imaging, comprising: a) administering to said human cancer patient a compound of general formula I:

[0338] [ka] (wherein n=14 to 16, R1 is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is H, unsaturated or saturated, linear or branched alkyl, alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl or alkylcarbonyloxyalkyl) administering an oral CT contrast agent comprising an iodinated fatty acid and / or an ester and / or a salt and / or a mixture thereof according to The administration of the oral CT contrast agent 18 performed at least 3 hours prior to administration of the FDG PET tracer; b) By intravenous injection 18 administering FDG to the human cancer patient; c) for the human cancer patient 18 performing an FDG PET-CT scan; d) detecting primary tumors and / or metastases from brown and / or beige tissue in said human cancer patient. 18 comparing both the PET and CT scans to assess co-localization of positive contrast enhancement of FDG and said CT contrast agent; A method comprising:

[0339] 17.General formula I:

[0340] [ka] (wherein n=14 to 16, R1 is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R2 is H, unsaturated or saturated, linear or branched alkyl, alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl or alkylcarbonyloxyalkyl) of an oral CT contrast agent comprising an iodinated fatty acid and / or an ester and / or a salt and / or a mixture thereof according to 18 1. Use in a PET-CT imaging method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue in a human cancer patient who has received prior administration of an FDG PET tracer, comprising: a) For the human cancer patient 18 performing an FDG PET-CT scan; b) determining whether the primary tumor and / or metastasis is brown and / or beige in said human cancer patient; 18 comparing both the PET and CT scans to assess co-localization of positive contrast enhancement of FDG and said CT contrast agent; Including, However, the CT oral contrast agent for use is 18 administered at least 3 hours before administration of the FDG PET tracer, In a method, use.

[0341] Overview Those skilled in the art will recognize that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from its spirit or essential characteristics. The invention also includes all steps, features, compositions, and compounds individually or collectively referred to or indicated herein, as well as any and all combinations or any two or more of said steps or features. Accordingly, the present disclosure should be considered in all aspects as illustrative and not restrictive, within the scope of the invention as indicated by the appended claims, and all changes that come within the meaning and range of equivalents are intended to be embraced therein.

[0342] The foregoing description will be more fully understood with reference to the following examples. However, such examples are illustrative of methods of practicing the invention and are not intended to limit the scope of the invention. [Example]

[0343] Example 1: In brown adipose tissue 18 FDG uptake leads to potentially erroneous results in PET-CT scans For patients undergoing PET scans 18 FDG is injected to image the tumor and / or metastases. 18 FDG uptake can occur in brown adipose tissue, leading to erroneous results (false positive and false negative) in PET-CT medical scans and / or the need to repeat the scan. Figure 1 shows FDG uptake in brown adipose tissue of human cancer patients. 18 An example of FDG uptake is shown in Figure 1A. 18FDG uptake is higher than in the primary tumor, which can lead to false-negative PET scan results in lung cancer patients. Figure 1B shows a pediatric cancer patient with very high BAT volume and / or activity. Such high BAT volume and / or activity can lead to false-positive and / or false-negative PET-CT scan results. In such cases, the patient usually requires repeat medical imaging procedures. Figure 1C shows asymmetry in BAT. 18 We present a case of FDG uptake, where the scan can lead to a false-positive result of tumor and / or metastasis in the neck.

[0344] Example 2: Cancer metastasis 18 Improving the specificity and positive predictive value of FDG PET-CT scans A syngeneic murine melanoma model (with dissemination of tumor metastases to the lungs) was induced by intravenous injection of B16F10 murine melanoma cancer cells in C57Bl / 6 mice. 19 days after cell injection, the animals 18 FDG was administered and a PET-CT scan was performed on each animal. One day later, a PET-CT contrast agent was administered via the oral route to the same animals. A second 18 An FDG PET-CT scan was performed, and the animals were then euthanized and a necropsy was performed on each animal.

[0345] 18 Evaluation of PET-CT scans for colocalization of positive contrast enhancement of FDG and PET-CT contrast agent allowed us to distinguish metastases from brown adipose tissue (Figures 2a and 3a). 18 The FDG signal was correctly attributed to BAT and improved the specificity and positive predictive value of PET-CT scans for tumor metastasis, which was confirmed by autopsy (Figs. 2b, c and 3b, c).

[0346] Based on autopsy (standard of truth), six mice presented a total of 24 metastases (average of four per mouse). 18In FDG PET-CT scans, four mice had positive signals in the BAT, which could be interpreted as metastases (false positives). 18 The positive predictive value (PPV) of FDG PET-CT scan was 85% (Figure 4). With the use of PET-CT contrast agents, the PPV was 100%. Therefore, CT contrast agents 18 It improves the PPV of FDG PET-CT scans by only 15%.

[0347] Example 3: Brown adipose tissue 18 Improving the sensitivity and negative predictive value of FDG PET-CT scans A syngeneic murine melanoma model (with dissemination of tumor metastases to the lungs) was induced by intravenous injection of B16F10 murine melanoma cancer cells in C57Bl / 6 mice. 19 days after cell injection, the animals 18 FDG was administered and a PET-CT scan was performed on each animal. One day later, a PET-CT contrast agent was administered via the oral route to the same animals. A second 18 A total of 12 FDG PET-CT scans were performed. 18 FDG PET-CT scans were performed (6 with and 6 without PET-CT contrast), and the animals were then euthanized and necropsies were performed.

[0348] Other than the presence of contrast enhancement due to PET-CT contrast agents 18 Evaluation of PET-CT scans for the absence of FDG uptake allowed for simple and robust detection of brown adipose tissue, increasing the sensitivity and positive predictive value of PET-CT scans or BAT.

[0349] In BAT 18 FDG uptake was present in a total of 9 of 12 PET-CT scans, however, all mice had BAT. 18Based on FDG uptake, the sensitivity of PET-CT scans for BAT was 75% (Figure 5). Based on PET-CT contrast agent uptake, the sensitivity for BAT was 100%. Thus, using the PET-CT contrast agent, the sensitivity of PET-CT scans for BAT in mice improved by 25%.

[0350] References 1. Al-Bulushi, NK, Bailey, D. & Mariani, G. The Medical Case for a Positron Emission Tomography and X-ray Computed Tomography Combined Service in Oman. Sultan Qaboos Univ. Med. J. 13, 491-501 (2013). 2. Alavi, A. et al. Positron emission tomography imaging in nonmalignant thoracic disorders. Semin. Nucl. Med.32, 293-321 (2002). 3. Carter, K. & Kotlyarov, E. Common causes of false positive F18 FDG PET / CT scans in oncology. Braz. Arch. Biol. Technol. - BRAZ ARCH BIOL TECHNOL 50, (2007). 4. Cypess, AM et al. Identification and Importance of Brown Adipose Tissue in Adult Humans. N. Engl. J. Med. 360, 1509-1517 (2009). 5. Frankl, J., Sherwood, A., Clegg, D. J., Scherer, P. E. & Oz, O. K. Imaging Metabolically Active Fat: A Literature Review and Mechanistic Insights. Int. J. Mol. Sci.20, (2019). 6. Hong, T. S. et al. Brown adipose tissue 18F-FDG uptake in pediatric PET / CT imaging. Pediatr. Radiol. 41, 759-768 (2011). 7. Steinberg, J. D., Vogel, W. & Vegt, E. Factors influencing brown fat activation in FDG PET / CT: a retrospective analysis of 15,000+ cases. Br. J. Radiol.90, 20170093 (2017). 8. Cohade, C., Osman, M., Pannu, H. K. & Wahl, R. L. Uptake in supraclavicular area fat (‘USA-Fat’): description on 18F-FDG PET / CT. J. Nucl. Med. Off. Publ. Soc. Nucl. Med.44, 170-176 (2003). 9. Long, N. M. & Smith, C. S. Causes and imaging features of false positives and false negatives on 18F-PET / CT in oncologic imaging. Insights Imaging 2, 679-698 (2011). 10. Wang, X. & Koch, S. Positron emission tomography / computed tomography potential pitfalls and artifacts. Curr. Probl. Diagn. Radiol. 38, 156-169 (2009). 11. Kolodny, G. & Williams, G. Method of Reducing Interferences in Positron Emission Tomography. (2008). 12. Allemann, E., Babic, A. & Vinet, L. Nanoemulsion of Iodinated Fatty Acids for Ct Imaging. (2019). 13. Huang, Y.-C. et al. The relationship between brown adipose tissue activity and neoplastic status: an (18)F-FDG PET / CT study in the tropics. Lipids Health Dis. 10, 238 (2011). 14. Chu, K., Bos, S. A., Gill, C. M., Torriani, M. & Bredella, M. A. Brown adipose tissue and cancer progression. Skeletal Radiol. 49, 635-639 (2020). 15. Bos, S. A., Gill, C. M., Martinez-Salazar, E. L., Torriani, M. & Bredella, M. A. Preliminary investigation of brown adipose tissue assessed by PET / CT and cancer activity. Skeletal Radiol. 48, 413-419 (2019). 16. Leitner, B. P. et al. Mapping of human brown adipose tissue in lean and obese young men. Proc. Natl. Acad. Sci. U. S. A. 114, 8649-8654 (2017). 17. Boellaard, R. et al. FDG PET / CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur. J. Nucl. Med. Mol. Imaging 42, 328-354 (2015). 18. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), & European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J. Hepatol. 64, 1388-1402 (2016). 19. DenOtter, T. D. & Schubert, J. Hounsfield Unit. in StatPearls(StatPearls Publishing, 2021); and Hounsfield unit | Radiology Reference Article | Radiopaedia.org. https: / / radiopaedia.org / articles / hounsfield-unit . 20. Giammarile, F. et al. Non-FDG PET / CT in Diagnostic Oncology: a pictorial review. Eur. J. Hybrid Imaging 3, 20 (2019).

Claims

1. 1. A PET-CT imaging agent for use in a PET-CT imaging method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue in a human cancer patient by PET-CT imaging, comprising: The PET-CT contrast agent has the general formula I: 【Chemistry 1】 (Wherein, n=14 to 16, R １ is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R ２ is H, unsaturated or saturated, straight or branched chain alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl, aryl, aryloxy, arylcarbonyl, arylcarbonylalkyl, heteroaryl, non-aromatic heterocycle, or alkylcarbonyloxyalkyl, which groups are optionally substituted with one or more substituents each independently selected from aryl groups, heteroaryl groups, halogen, hydroxy, alkyl groups, alkoxy groups, aryloxy groups, and non-aromatic heterocycles, each of which halogen substituents is independently selected from F, Cl, Br, and I, and when multiple iodine atoms are present, no two iodine atoms may be in either geminal or vicinal positions. and / or esters and / or salts and / or mixtures thereof according to The PET-CT imaging method includes: a) administering the PET-CT imaging agent to the human cancer patient; b) administering 2-[fluorine-18]fluoro-2-deoxy-D-glucose ( ... １８ administering a PET tracer (FDG); c) for the human cancer patient １８ performing an FDG PET-CT scan; A PET-CT contrast agent comprising:

2. The PET-CT contrast agent of claim 1, wherein the R 2 group is substituted with 1 to 5 substituents.

3. The PET-CT contrast agent of claim 1, wherein the R 2 group is substituted with 1, 2, 3, or 4 substituents.

4. The use is in a method for identifying non-malignant and non-metastatic tissues in a cancer patient and / or for identifying malignant or metastatic tissues, the method comprising the steps of: d) the above １８ identifying areas where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; e) １８ Although there is positive contrast enhancement of FDG, １８ identifying areas without co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; f) assigning the co-localized areas identified in step d) as areas of no malignancy or metastasis, and assigning the non-co-localized areas identified in step e) as areas of possible malignancy or metastasis; The PET-CT contrast agent according to any one of claims 1 to 3, wherein the following is performed.

5. The PET-CT contrast agent according to any one of claims 1 to 3, wherein the use is selected from the following (I) to (VIII): (I) The use is a method for evaluating the prognosis of cancer, which comprises carrying out the method steps a) to c) of claim 1 and then carrying out the following steps: d) comparing the PET-CT scans with those of healthy individuals; e) the above １８ determining areas of co-localization of positive contrast enhancement of FDG and the PET-CT contrast agent as highly active BAT; f) There is positive contrast enhancement of the PET-CT contrast agent １８ determining an area where no FDG is present as a BAT; g) assessing the prognosis of the cancer to be treated based on the results obtained in steps d), e) and f); will be carried out, (II) The use is in a method for diagnosing cancer, which comprises the following additional steps after carrying out the method steps a) to c) of claim 1: d) １８ Although there is positive contrast enhancement of FDG, １８ identifying areas without co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; e) １８ assigning areas with positive FDG enhancement but no co-localized positive enhancement as areas of possible malignancy or metastasis; f) diagnosing cancer by assessing the localization of the area identified in step e); will be carried out, (III) The use is in a method for staging or restaging a tumor, which comprises, after carrying out steps a) to c) of the method of claim 1, carrying out the following additional steps: d) １８ Although there is positive contrast enhancement of FDG, １８ identifying areas without co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; e) １８ Although there is positive contrast enhancement of FDG, １８ assigning areas without co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent as areas of possible malignancy or metastasis; f) assigning the patient to an appropriate stage of the TNM system by assessing the location and volume and / or surface area of ​​the possible areas identified in step e), lymph node involvement and / or the presence of metastases; will be carried out, (IV) The use is a method for evaluating the efficacy of a therapy or the progression of a cancer, which comprises the following additional steps after carrying out the method steps a) to c) of claim 1: d) １８ Although there is positive contrast enhancement of FDG, １８ identifying areas lacking co-localization of positive contrast enhancement of FDG and the PET-CT contrast agent as areas likely to harbor malignant tumors or metastases; e) １８ determining the volume and / or surface area of ​​identified areas with positive FDG enhancement but no co-localized positive enhancement; f) optionally subjecting the patient to anti-cancer therapy; g) repeating steps a) to e); h) assigning an effective therapy and / or lack of cancer progression if performed if the volume and / or surface area of ​​the area identified according to step g) is equal to or smaller than the volume and / or surface area of ​​the area identified according to step e), and assigning an ineffective therapy and / or cancer progression if performed if the volume and / or surface area of ​​the area identified according to step g) is greater than the volume and / or surface area of ​​the area identified according to step e). will be carried out, (V) The use is in a method for determining BAT activity, which comprises the following additional steps after carrying out the method steps a) to c) of claim 1: d) the above １８ identifying areas of co-localized positive contrast enhancement of FDG and the PET-CT contrast agent, as well as areas of positive contrast enhancement of the PET-CT contrast agent alone; e) as identified in step d). １８ determining the volume and / or surface area of ​​the area where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; f) determining the volume and / or surface area of ​​the area with positive contrast enhancement of only said PET-CT contrast agent as identified in step d); g) calculating the ratio of the volume and / or surface area determined in step e) divided by the volume and / or surface area determined in step f); h) comparing said ratio with a reference ratio determined as an average value by carrying out steps a) to g) on ​​a population of cancer patients; i) assigning increased BAT activity if the determined ratio is higher than the reference ratio, assigning normal or reduced BAT activity if the determined ratio is approximately the same as the reference ratio, and assigning reduced BAT activity if the determined ratio is lower than the reference ratio; will be carried out, (VI) The use is a method for cancer prognosis, which comprises the following additional steps after carrying out steps a) to i) of (V): j) assigning a poor prognosis if step i) assigns a decreased BAT activity in the patient suffering from hormone-dependent cancer and assigning a poor prognosis if step i) assigns an increased BAT activity in the patient suffering from hormone-independent cancer. will be carried out, (VII) The use is a method for cancer prognosis, which comprises the following additional steps after carrying out steps a) to c) of the method of claim 1: d) the above １８ determining the volume and / or surface area of ​​the area of ​​positive contrast enhancement where there is co-localization of positive contrast enhancement of FDG and said PET-CT contrast agent; e) comparing the determined volume and / or surface area with a reference value determined as an average value by carrying out steps a) to d) on a population of cancer patients; f) assigning a poor prognosis if the quantified volume and / or surface area is lower than the reference value in patients suffering from hormone-dependent cancer, and assigning a poor prognosis if the quantified volume and / or surface area is higher than the reference value in patients suffering from hormone-independent cancer; will be carried out, (VIII) The use is a method for cancer prognosis, which comprises the following additional steps after carrying out the method steps a) to c) of claim 1: d) determining the volume and / or surface area of ​​positive contrast enhancement of the PET-CT contrast agent; e) comparing the determined volume and / or surface area with reference values ​​derived from a healthy individual or a group of healthy individuals; f) assigning a poor prognosis if the quantified volume and / or surface area is lower than the reference value in patients suffering from hormone-dependent cancer, and assigning a poor prognosis if the quantified volume and / or surface area is higher than the reference value in patients suffering from hormone-independent cancer; will be carried out.

6. 1. A PET-CT imaging agent for use in a method for assessing the efficacy of an anti-cancer treatment, comprising: The method comprises the steps of: 1) administering a PET-CT imaging agent as described in any one of claims 1 to 3 to a patient or group of patients prior to the administration of an anti-cancer treatment; 2) After at least 3 hours, 2-[fluorine-18]fluoro-2-deoxy-D-glucose ( １８ FDG) to 3) １８ performing an FDG PET-CT scan; 4) administering one or more anti-cancer treatments; 5) administering a PET-CT contrast agent as described in claim 1 to a patient after anti-cancer treatment; 6) After at least 3 hours, １８ administering FDG; 7) １８ performing an FDG PET-CT scan; 8) In the PET-CT scan of step 3) １８ determining the volume and / or surface area of ​​areas with positive FDG contrast enhancement but without co-localized positive contrast enhancement; 9) In the PET-CT scan of step 7) １８ determining the volume and / or surface area of ​​areas with positive FDG contrast enhancement but without co-localized positive contrast enhancement; 10) comparing the volume and / or surface area determined in step 8) with the volume and / or surface area determined in step 9); The method further comprises 11) evaluating the efficacy of the anti-cancer treatment if the comparison in step 10) does not show an increase in volume and / or surface area from step 8) to step 9); or The method further comprises 11) performing steps 1) to 10) on a different patient or group of patients, but administering a placebo or reference treatment instead of the anti-cancer treatment in step 4); 12) assigning efficacy of the anti-cancer treatment if the comparison of step 10) in the anti-cancer treated patient or patient group shows an increase in volume and / or surface area from step 8) to step 9) that is less than that obtained in the comparison of step 10) in the placebo patient or patient group, or, if a reference treatment is used in step 11), assigning efficacy of the anti-cancer treatment if the comparison of step 10) in the anti-cancer treated patient or patient group shows an increase in volume and / or surface area from step 8) to step 9) that is less than or equal to that obtained in the comparison of step 10) in the patient or patient group receiving the reference treatment. Including, PET-CT contrast agent.

7. The PET-CT contrast agent is administered orally; The PET-CT contrast agent according to any one of claims 1 to 6.

8. The PET-CT contrast agent of claim 7, wherein the orally administered PET-CT contrast agent is adapted for non-invasive in vivo imaging, quantification and / or monitoring of the activity of brown and / or beige adipose tissue (BAT) in the human cancer patient.

9. The PET-CT contrast agent of claim 7, wherein the orally administered PET-CT contrast agent is in the form of a biocompatible formulation.

10. 10. The PET-CT contrast agent of claim 9, wherein the biocompatible formulation is an emulsion.

11. the emulsion comprises a biocompatible emulsifier selected from the group comprising lecithin, polyoxyethylene sorbitan fatty acid esters, sucrose stearate, polyoxyethylene stearate, sucrose esters, sorbitan esters and / or mixtures thereof; The PET-CT contrast agent according to claim 10.

12. The amount of the biocompatible emulsifier in the emulsion is between 3 and 50% (w / w) of the total emulsion. The PET-CT contrast agent according to claim 11.

13. The amount of the biocompatible emulsifier in the emulsion is between 5 and 25% (w / w) of the total emulsion. The PET-CT contrast agent according to claim 11.

14. 14. The PET-CT contrast agent of any one of claims 7 to 13, wherein the orally administered PET-CT agent is administered at a dose corresponding to between 0.004 and 0.5 mg of iodine per gram of body weight.

15. A PET-CT contrast agent according to any one of claims 7 to 13, wherein the orally administered PET-CT agent is administered at a dose corresponding to between 0.02 and 0.2 mg of iodine per gram of body weight.

16. 16. The PET-CT contrast agent of any one of claims 1 to 15, wherein the cancer is selected from the group consisting of lung, colorectal, breast, gynecological, head and neck, esophageal, gastric, biliary tract, follicular and medullary thyroid, and pancreatic cancer, leukemia, melanoma, lymphoma, multiple myeloma, sarcoma, pheochromocytoma, lipoma, liposarcoma, and primary brain tumors.

17. 17. The PET-CT imaging agent of any one of claims 1 to 16, adapted for use in human cancer patients under the age of 18.

18. 18. The PET-CT imaging agent of any one of claims 1 and 7 to 17, adapted for cancer detection and / or cancer staging and / or cancer restaging and / or for assessing the success of a treatment of said cancer in said human cancer patient.

19. 1. A PET-CT contrast agent for use in a PET-CT imaging method for distinguishing primary tumors and / or metastases from brown and / or beige adipose tissue in a human cancer patient, comprising: The PET-CT contrast agent is General formula I: 【Chemistry 2】 (Wherein, n=14 to 16, R １ is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R ２ is H, unsaturated or saturated, straight or branched chain alkyl, alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl, aryl, aryloxy, arylcarbonyl, arylcarbonylalkyl, heteroaryl, non-aromatic heterocycle, or alkylcarbonyloxyalkyl, which groups are optionally substituted with one or more substituents each independently selected from aryl groups, heteroaryl groups, halogen, hydroxy, alkyl groups, alkoxy groups, aryloxy groups, and non-aromatic heterocycles, each of which halogen substituents is independently selected from F, Cl, Br, and I, and when multiple iodine atoms are present, no two iodine atoms may be in either geminal or vicinal positions. and / or esters and / or salts and / or mixtures thereof according to The method comprises: a) orally administering the oral PET-CT contrast agent to the human cancer patient; b) administering 2-[fluorine-18]fluoro-2-deoxy-D-glucose ( ... １８ administering a PET tracer (FDG); c) administering to the human cancer patient １８ Colocalization of positive contrast enhancement between FDG and the PET-CT contrast agent １８ performing an FDG PET-CT scan; Including, PET-CT contrast agent.

20. The PET-CT contrast agent of claim 19, wherein the R 2 group is substituted with 1 to 5 substituents.

21. The PET-CT contrast agent of claim 19, wherein the R 2 group is substituted with 1, 2, 3, or 4 substituents.

22. 1. A pharmaceutical composition for use in the detection of cancer, and / or the staging and / or restaging of cancer, and / or the evaluation of the performance of a cancer treatment in a human cancer patient, and / or the development of a treatment against cancer, comprising: The pharmaceutical composition comprises: General formula I: 【Transformation 3】 (Wherein, n=14 to 16, R １ is H or I, provided that the number of iodine atoms is 1 to 6 and the iodine atoms are neither geminal nor vicinal; R ２ is H, unsaturated or saturated, straight or branched chain alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxypolyalkyleneoxyalkyl, aryl, aryloxy, arylcarbonyl, arylcarbonylalkyl, heteroaryl, non-aromatic heterocycle, or alkylcarbonyloxyalkyl, which groups are optionally substituted with one or more substituents each independently selected from aryl groups, heteroaryl groups, halogen, hydroxy, alkyl groups, alkoxy groups, aryloxy groups, and non-aromatic heterocycles, each of which halogen substituents is independently selected from F, Cl, Br, and I, and when multiple iodine atoms are present, no two iodine atoms may be in either geminal or vicinal positions. and / or esters and / or salts and / or mixtures thereof according to The use is in a method as specified in any one of claims 1 to 21. Pharmaceutical compositions.

23. 1. A pharmaceutical composition for use in the detection of cancer, and / or the staging and / or restaging of cancer, and / or the evaluation of the performance of cancer treatments in human cancer patients, and / or the development of treatments against cancer, comprising 2-[fluorine-18]fluoro-2-deoxy-D-glucose ( １８ FDG), 22. A pharmaceutical composition, wherein the use is in a method as specified in any one of claims 1 to 21.

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