(19) TZZ Z _T

(11) EP 2 907 526 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 19.08.2015 Bulletin 2015/34 A61K 49/04 (2006.01) A61K 51/04 (2006.01) A61K 49/06 (2006.01) (21) Application number: 15155866.5

(22) Date of filing: 20.06.2008

(84) Designated Contracting States: (72) Inventor: Wiebelitz, Ulrike AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 13158 Berlin (DE) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR (74) Representative: Kilger, Ute Boehmert & Boehmert (30) Priority: 22.06.2007 EP 07110922 Anwaltspartnerschaft mbB Patentanwälte Rechtsanwälte (62) Document number(s) of the earlier application(s) in Pettenkoferstrasse 20-22 accordance with Art. 76 EPC: 80336 München (DE) 12199299.4 / 2 572 735 12168380.9 / 2 514 442 Remarks: 08774183.1 / 2 170 405 This application was filed on 20-02-2015 as a divisional application to the application mentioned (71) Applicant: mivenion GmbH under INID code 62. 10115 Berlin (DE)

(54) Imaging diagnostics by combining contrast agents

(57) The present invention relates to the use of a combination of several contrast agents having different imaging properties with respect to imaging representation. EP 2 907 526 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 907 526 A1 2

Description from suspect lesions and to prepare and assess these samples histopathologically. [0001] The present invention relates to the use of a [0005] MRI examination of the female breast has very combination of several contrast agents having different high sensitivity in comparison to other imaging modali- imaging properties. 5 ties. Due to this modality, it is possible to detect different [0002] Chronic diseases are an important field of ap- forms of breast cancer at an early stage. A particular plication for imaging diagnostics. The two most frequent advantage of MRI is the fact that imaging examination is chronic diseases, cardiovascular diseases and tumour not complicated in a significant way by non-tumerous tis- diseases, alone account for the greater part of the 800 sue alterations, such as e.g. surgical cicatrices, tissue million imaging diagnoses which are carried out every 10 alterations by radiological treatment, prostheses or mas- year worldwide. The majority of examinations are ultra- topathically altered glandular tissue. Due to these char- sonic examinations, X-ray examinations, such as CT and acteristics, MRI has meanwhile found a large range of MRI examinations, but also nucleomedical and optical applications. methods are often used. For all of these examination [0006] The high sensitivity of MRI of the breast is, how- methods, contrast agents are clinically available. Con- 15 ever, associated with low specificity. Low specificity im- trast agents provide specific information determined by plies that almost all malignant tumours are detected but their pharmacokinetic and pharmacodynamic properties. that, at the same time, many foci which, in the course of However, imaging examination alone often allows only subsequent examinations, are found to be harmless, are for little diagnostic information. Due to this reason, it is represented as malignant tumours. The reason for this often necessary to carry out various examinations with 20 is that MRI uses contrast agents which improve the meth- the same modality and different contrast agents or to od to a degree that allows to show even minor irregular- carry out different examinations with different modalities, ities in the breast tissue to be examined. These contrast in order to allow a reliable diagnosis. This procedure in- agents are not appropriate to make a satisfactory distinc- volves high costs and strain/stress for the patient. Fur- tion between benign and malignant lesions. As a conse- thermore, this approach is time-consuming and, the be- 25 quence of the diagnostic results, the physician has to ginning of a necessary therapy is often delayed due to initiate further examinations which are to assess the pre- the fact that several diagnostic examinations are re- sumptive diagnostic findings in greater detail. On the one quired. A further disadvantage is the assignment of di- hand, further imaging methods are applied, on the other agnostic signals from different imaging examinations. hand, it is possible to make an MRI-based biopsy of the Very often, it is not possible to correlate suspect lesions 30 suspect tissue and establish an exact diagnosis by his- of one examination to the lesions detected in another tological examination. The fact that this is a method of examination, which considerably complicates the diag- high technical standard involving high costs is one of the nosis for the physician. The necessity to carry out differ- reasons why MRI imaging has not yet been established ent diagnostic examinations in order to establish a relia- as standard method for breast cancer diagnosis. As to ble diagnosis can be illustrated by the imaging diagnos- 35 clinical application of CT, the situation is similar. CT also tics of tumours, particularly the imaging diagnostics of plays a major role in tumour diagnosis. For example, the breast cancer. CT-contrast agent Ultravist® is used for imaging CT di- [0003] Breast cancer is one of the most frequent tu- agnosis of liver tumours. This method also shows minor mours and the most frequent tumour disease with wom- specificity with respect to the contrast agents based di- en. Improved early diagnosis, such as screening mam- 40 agnosis. Thus, itis acentral task to improve the specificity mogram, and complex treatment protocols allowed a de- of diagnostic imaging in order to make it widely applica- crease in mortality over the last years. Nonetheless, a ble. great number of breast cancer cases are only detected [0007] One possibility to improve the specificity of in- at a late stage. Hence, the early diagnosis of tumours is formation provided by an imaging modality is to use im- a great challenge. This is particularly important as the 45 proved signal altering or signal modulating contrast growth of small tumours is limited to the organ so that agents. Today, contrast agents are clinically available for there is hope to remove the tumour completely and to most of the imaging methods. These contrast agents are conserve the organ if tumours are detected in early stag- selected in such a way that, on the one hand, their ap- es. Medical methods available up to present meet this plication is acceptable with humans and that, on the other requirement only inadequately. Hence, it is important to 50 hand, they can interact with the physical signal of the provide improved methods of early and reliable diagno- relevant examination modality in a very specific manner. sis. Most empirical data regarding the application of contrast [0004] Today, the physician can use various diagnostic agents relate to X-ray-based CT examination methods. methods with the imaging techniques playing a major Diagnostic radiology uses contrast agents which atten- role. Among the imaging techniques, ultrasonic diagno- 55 uate the X-rays. These are, amongst others, substances sis, CT, MRIand nucleomedical techniques, suchas PET with a great number of elements having high electron and SPECT, are the most relevant techniques. With un- density, such as iodine. These contrast agents can be cleardiagnostic findings, the aim is to take tissue samples applied in a variety of ways in humans, however, the most

2 3 EP 2 907 526 A1 4 frequent applications are applications in which the con- This phase can be followed by a rapid but often incom- trast agents are introduced by bolus injection into the plete washout phase. The signal in the lesions can be blood circulation. By applying contrast agents in this way, inferior to the signal in the surroundings, as, due to the it is possible to make the blood flow in a specific organ disturbed barrier function, the wash-out process in the visible for the duration of the examination. This applica- 5 lesion can occur faster than in the healthy tissue where tion form of contrast agents allows to obtain important the intact barrier reduces the velocity of back flow. Back information on the anatomy, morphology and function of flow is however always caused by fast decrease of the specific organs. Thus, it is possible to obtain information ECCM concentration in the blood. This is a characteristic on the condition of a blood vessel by detecting a contrast property of the ECCM used according to the invention. agent in this blood vessel and by visualizing the vessel 10 Fast elimination from blood circulation requires incom- lumen. Existing constrictions of the coronary arteries can plete and loose binding of plasma protein and is ensured be made visible by coronary angiography without diffi- by renal and/or hepatic elimination capacity, in contrast culties, thus, leading to the diagnosis of coronary steno- to ECCM, lesion-specific contrast agents (LSCM) used sis. Another parameter providing significant diagnostic according to the invention are characterised in that they data is the velocity with which the contrast agent applied 15 can interact with a specific target structure in the organ- flows into the organ. Thus, it is possible to draw conclu- ism or are altered by said specific structures in such a sions with respect to the blood circulation within a par- way that they can be visualised in an imaging technique ticular organ. as a consequence of the interaction or alteration. A fur- [0008] The application of contrast agents is as impor- ther property by which they can be distinguished from tant in MRI as it is in radiodiagnostics. For X-ray-based 20 ECCM is their longer retention in blood circulation. This examinations as well as for MRI examinations, a great property can be achieved, for example, by ensuring that number of different contrast agents is available to the the relevant LSCM are characterised by a stronger plas- physician. However, all of these contrast agents are op- ma protein binding of more than 90%. The characteristic timised for specific application purposes. Extracellular properties of LSCM can easily be detected byin-vivo contrast agents (ECCM) play a major role in the detection 25 imaging studies in animals or human. A continuous ac- of tissue lesions, such as tumours, diseases of the central cumulation in the target lesion indicates a LSCM. nervous system (CNS) and diseases of the cardio-vas- [0009] The most important ECCM in MRI is gadolin- cular system. These contrast agents are optimised in ium-DTPA (Gd-DTPA). Gd-DTPA is a paramagnetic sub- such a way that their concentration in the blood is rapidly stance which leads to a reduction of the T1 relaxation reduced from a maximum concentration to a minimum 30 time of the surrounding tissue. It is a substance with low concentration within very few minutes after their applica- molecular weight, which does not interact with structures tion (alpha slope, blood kinetics). Furthermore, they are of the organism and is not altered by these. Due to this characterised in that they have plasma protein binding property, it is capable of leaving the capillary system even of less than 90%, preferably of less than 70%. ECCM if the capillary barrier is intact and vascular permeability can easily be selected from a series of different contrast 35 is normal. Having left the capillary system, Gd-DTPA agents by in-vivo imaging studies in animals or human. spreads in the extravasal space. Many diseases, such In these in-vivostudies a fast decline of theimaging signal as e.g. tumour diseases, inflammatory organ alterations over the target lesion or reference regions indicates a or tissue injuries due to apoplexia result in damage of characteristic of ECCM. Due to their small molecular size the capillary barrier. If patients suffering form such dis- and the incomplete binding to plasma proteins, they eas- 40 eases are subjected to MRI examinations with the con- ily pass the capillary barrier. Another significant property trast agent Gd-DTPA, the contrast agent extravasates to of the ECCM is the lack of interaction with biological struc- an increased degree in areas where the capillary barrier tures. ECCM do not bind to specific structures in the le- is damaged. The concentration in the tissue is increased sion to be examined and are not altered by these struc- particularly in these areas, which is noticeable by an in- tures. Due to these properties, they can pass the capillary 45 creased signal in the MRI image. This effect is followed barriers in both directions and, thus, they are capable of by an increased back diffusion also known as wash-out demarcating suspect lesions from the surrounding phenomenon. This characteristic behaviour, which is al- healthy tissue. This process is known as extravasation so known as "wash-in/wash-out" phenomenon, can be and occurs also in an intact capillary system, though with used in MRI diagnosis in various ways, e.g. for the de- clearly reduced velocity. In particular with tumour diseas- 50 tection of tumours with high scanning speeds during the es, diseases of the central nervous system and diseases injection of contrast agent in MRI. In particular the imag- of the cardio-vascular system, the capillary barrier is de- ing diagnostics of suspect tissue alterations of the female fect and ECCM leakage occurs preferably at these sites. breast proved that the "wash-in/wash-out" phenomenon Extravasation of the ECCM results in a signal increase allows to detect probably all malignant breast lesions in the lesion in comparison to the healthy surroundings. 55 above a certain size. The method, however, also has a Within the first minutes after injection of an ECCM, signal great disadvantage. In addition to the existing malignant increases of up to 100% can be observed. This first phase tumours, many benign foci are detected. These are var- of the extravasation process is also known as wash-in. ious benign tissue alterations of different kinds which

3 5 EP 2 907 526 A1 6 bear no risk for the patients. enhancing the result obtained with the other contrast [0010] So far, no method is known which would en- agent. Used in combination according to the invention, hance the specificity of highly sensitive imaging methods ECCM and LSCM are contrast agents with complemen- in a satisfactory way. tary action properties. [0011] A possibility to enhance the specificity of imag- 5 [0013] Thus, subject matter of the present invention is ing examination methods consists in carrying out differ- an extracellular contrast agent (ECCM) for the diagnosis ent contrast agent-based examinations. In the literature, of lesions in combination with a lesion-specific contrast methods are known wherein the suspect disease lesions agent (LSCM). According to the invention, the individual were characterised by subsequently using two different contrast agents of the combination of ECCM and LSCM MRI contrast agents. For this monomodal method, the 10 may be imaging contrast agents for a single synthetic examination was carried out in two steps. First, an LSCM imaging method (monomodal) or multiple synthetic im- was applied. Due to the long retention period, the con- aging methods (polymodal). centration of an ECGM could only be examined by a de- [0014] The combination of ECCM and LSCM accord- layed second examination. This approach has the deci- ing to the invention envisages a fixed time sequence for sive disadvantage that by carrying out the examinations 15 the application of the individual substances. In the case separately, an overlap of the two signals is possible only of the monomodal technique, the ECCM is administered in a limited way. Thus, the method known from literature first and the LSCM is administered subsequently. The loses some of its sensitivity and specificity and offers no LSCM is administered at the earliest when the ECCM advantage [Marcarini L. et. al; Radiol. Med. (2006) 111: level in the blood has reached a level that allows detecting 1087-1102]. 20 the LSCM. [0012] Surprisingly, it was found that the use of ECCM [0015] Thus, subject matter of the present invention is in combination with at least one further imaging contrast also an extracellular contrast agent (ECCM) for the di- agent or signalling substance which tends to concentrate agnosisof lesions, wherein,in the case of the monomodal specifically in the disease lesion (lesion-specific contrast technique, the ECCM is provided for in a manner suited agent/LSCM) is a completely new imaging method hav- 25 for the intended use for administration as first contrast ing a markedly higher specificity than the application of agent and the LSCM is provided for in a manner suited anECCM alone.The combination of theinvention ischar- for the intended use as second contrast agent to be ad- acterised in that the ECCM and the LSCM are applied at ministered after the ECCM level in the blood has declined the same time or the LSCM is applied with a short time to a level that allows the detection of the ECCM. In the delay of 30 minutes maximum, preferably of 20 minutes 30 case of the polymodal technique, the contrast agents maximum, most preferably of 10 minutes maximum after may be provided for in a manner suited for the intended the application of the ECCM. Thus, the method of the use in such a way that they can be administered at the invention allows to interpolate the different imaging sig- same point in time. In the case of the polymodal tech- nals and to achieve a lesion diagnosis of high sensitivity nique, they may, however, be provided for in a manner and high specificity. Interpolation means that, in a given 35 suited for the intended use in such a way that the LSCM examination area/region, at least two signals differing is prepared for administration as first contrast agent and from each other can be/are related in space and in time. the ECCM for administration as second contrast agent. Thus, the invention resolves the disadvantages of the This approach surprisingly provides the possibility to in- state of the art - with diagnostic methods being carried vestigate the distribution of the disease in the whole body out independently from one another by combining ECCM 40 as the first step, and to perform detailed characterisation and LSCM which allows a useful interpolation of the dif- of the suspicious lesions with ECCM as the second step. ferent imaging signals. Diagnostic methods being carried [0016] Preferably, in a polymodal technique, the LSCM out independently from one another means, that the pa- is administered as first contrast agent and the ECCM is tient is moved from the examination table in between the administered as second contrast agent, where the image diagnostic methods. The ECCM is used to detect the45 registration of the LSCM is performed first, and the image lesions, whereas the LSCM is used to characterise the registration for the ECCM is performed second. As an lesions. By using this method, the number of false posi- example, in the combination of 18F-Fluordeoxyglucose tive diagnostic findings can be decreased significantly (FDG)as LSCMfor PET imaging with Ultravist ®as ECCM and physician as well as patient can be spared unnec- for CT imaging for a combined PET/CT imaging of can- essary examinations. Unexpectedly, the present inven- 50 cer, after administration of FDG and subsequent admin- tion provides for an increased diagnosis sensitivity and istration of Ultravist ®, the PET exam with image registra- specificity in comparison with the state of the art, wherein tion of the LSCM is performed. As FDG is accumulated images from independent examinations are merely spa- not only in e.g. cancer cells, but also in a variety of normal tially overlaid. The present invention furthermore allows cells (e.g. brain) and cells affected by other disease (e.g. for adjusting examination parameters such as the spatial 55 inflammation), the subsequent CT imaging for image reg- area which lies within the focus of the diagnostic appa- istration of the ECCM is performed only in the regions ratus or the irradiation intensity as a consequence to the with increased FDG uptake to allow a high-resolution im- result obtained by one of the contrast agents, thereby aging with a slice collimation of 2 mm or less, preferably

4 7 EP 2 907 526 A1 8 of 1 mm or less in CT for detection of subtle morphologic hydrophilicity is significantly delayed. Hydrophilicity of signs, e.g. of cancer. the EGCM of the invention is characterised by a distri- [0017] Preferably, the combination of the invention is, bution coefficient of log P < -2 (less than minus two in n- however, used in such a way that the ECCM is adminis- butanol/water), preferably by a distribution coefficient of tered first in order to detect suspect lesions in the relevant 5 log P < -3 (less than minus three in butanol/water). organs. The LSCM is then used in order to provide infor- [0021] ECCM of the invention are contrast agents for mation with respect to the kind of lesions based on its MRI, X-ray-based techniques such as CT, optical tech- concentration in said lesions. niques, optoacoustical techniques, ultrasonic techniques [0018] In the case of the polymodal technique, both and nucleomedical techniques. They are characterised contrast agents can be administered sequentially - like 10 in that they do not interact with structures of the organism in the monomodal technique - and simultaneously. Thus, after injection and in that they are not altered in their subject matter of the present invention is an extracellular signalling property by interaction with structures of the contrast agent (ECCM) for the diagnosis of lesions in organism. Their movement is determined by the velocity combination with LSCM, wherein in the case of the pol- of distribution and elimination. After reaching the maxi- ymodal method 15 mum concentration in the blood, the process of distribu- tion is completed and substance levels which are no long- - either the ECCM is prepared for administration as er sufficient for imaging are reached preferably after 10 first contrast agent and the LSCM is prepared as minutes. Hence, 30 minutes after injection at the latest, second contrast agent to be administered after the preferably 20 minutes after injection, most preferably af- level of ECCM in the blood has declined to a level 20 ter 10 minutes after injection, the concentration of the that allows the detection of the ECCM, or contrast agents of the invention in the blood circulation is reduced to a degree that the LSCM can be applied. - the ECCM and the LSCM are prepared for simulta- [0022] ECCM are particularly preferred which exhibit neous administration. a blood concentration that is reduced to a level allowing 25 administration of the LSCM after 30 minutes at the latest, [0019] The contrast agents may also be prepared in particularly preferred after 10 to 15 minutes. Animal im- such a way that the LSCM is prepared for administration aging studies can be applied to discriminate between EC- as first contrast agent and the ECCM for administration CM and LSCM. A fast decline of the imaging signal over as second contrast agent. Subject matter of the present the target lesion or reference region is a characteristic of invention is also a method for the diagnosis of lesions, 30 ECCM, whereas LSCM exhibits a continuous accumu- wherein an extracellular contrast agent (ECCM) is ad- lation in the target lesion over more than 30 to 60 minutes ministered in combination with a lesion-specific contrast after application. agent (LSCM) and, preferably, the imaging signals are [0023] Thus, in the present invention, the ECCM and interpolated immediately. LSCM are defined by their different target lesion elimi- [0020] The ECCM of the invention are signaling and 35 nation times. Hereby, the absolute elimination time of signal-modulating substances for synthetic imaging tech- each contrast agent from the target lesion is not of par- niques which, after having been applied to humans, rap- ticular significance, but rather the relative elimination idly reach a high peak concentration in the blood due to times of the contrast agents to be used as ECCM/LSCM the bolus-like injection which is normally used and the pair. This means that the ECCM is eliminated in 20 % of high concentration of said ECCM rapidly declines from 40 the time or less, more preferably in 10 % of the time or this high level by their spreading into the whole organism less, with respect to the elimination time from the target (alpha slope, elimination kinetics). In general, this proc- lesion of the LSCM, wherein preferably, the time differ- ess is terminated within 5 to 10 minutes after application. encebetween the eliminationof the ECCMand the LSCM In general, after 5 to 10 minutes after application the sub- to a level of 10 % of the maximum concentration of ECCM stance levels in circulation are below a level allowing im- 45 and LSCM in the target lesion is at least 20 minutes, more aging detection. Renal and hepatitic elimination, or a preferably at least 30 minutes. Consequently, many con- combination of both, is decisive for further clearance of trast agents may be used both as LSCM or ECCM, de- substance levels from the circulation. For fast elimination pendingwhether the secondcontrast agent which is used from blood circulation, the imaging substances must be in combination therewith has a slower or more rapid elim- of small molecular size. The elimination of substances 50 ination. Hereby, the tissue type which is comprised by with a molecular weight of more than 2,000 to 5,000 is the area of interest will have to be accounted for, as sev- significantly slower compared to the elimination of sub- eral contrast agents show different elimination times in stances with a molecular weight of up to 1 ,000 g/mol. different tissue types. In general, a person skilled in the Hence, the ECCM of the invention have a molecule size art will recognize combinations of contrast agents which of less than 2,000 g/mol, preferably of less than 1 ,000 55 represent appropriate ECCM/LSCM pairs for a given ap- g/mol. Another important property of the ECCM is their plication and a given tissue type, as the elimination be- hydrophilicity. Substances having high hydrophilicity are haviour of most contrast agents has already been de- eliminated fast. The elimination of substances having low scribed in great detail. In some cases however, a simple

5 9 EP 2 907 526 A1 10 experiment will have to be conducted in which the elim- DTPA-BMA, DPDP, TMT and HPDO3A, gadubotrol ination behaviour of a contrast agent in a certain tissue (Gadovist®), gadopentetatic acid/dimeglumine salt type is monitored. The skilled person, such as a radioio- (Magnevist®), gadobenic acid (Multihance®), gadodi- gist, is trained to carry out such experiments routinely. amide (Omniscan), gadoxetic acid/disodium salt (Primo- In this context, the term "eliminated" or "elimination"5 vist®; Gd-EOB-DTPA), and gadoteridol (Prohance®). means that the level of contrast agent in a given area of [0027] Gadubotrol (Gadovist®), gadopentetatic ac- diagnostic interest has reached a vaiue of 10% or less id/dimeglumine salt (Magnevist®), gadobenic acid (Mul- of the maximum level after injection. tihance®), gadodiamide (Omniscan), gadoxetic acid/dis- [0024] ECCM are substances, contrast agents or ef- odium salt (Primovist ®; Gd-EOB-DTPA), and gadoteridol fector molecules, preferably selected from the group10 (Prohance®) are particularly preferred. comprising: [0028] Subject matter of the invention are ECCM con- taining superparamagnetic iron oxide particles. These - metal complexes with paramagnetic metals, are biocompatible and acceptable due to the stabilizing protectivecoating. Theiron oxide particles with protective - superparamagnetic, ferromagnetic or ferrimagnetic 15 coating have a diameter of 20 -500 nm, preferably of 20 iron oxide particles with polymeric protective coating, - 200 nm. Protective coatings consists of polymers, in particular polysaccharides such as dextran. SPIOs, US- - complex-bound, chelator-bound and covalently PIOs, MIONs are particularly preferred. bound radioactive nuclides, [0029] Subject matter of the invention are ECCM con- 20 taining chromophores or fluorophores. Chromophores or - gas-filled, polymeric microparticles or microvesicles, fluorophores are structures which have an extended sys- tem of delocalized electrons, which absorb and fluoresce - gas precursors, within a spectral range of 300 -1400 nm. Chromophores or fluorophores with an absorption and/or emission max- - organic, metallo-organic or anorganic chromo-25 imum of 400 - 600 nm (visible fluororescence) as well as phores or fluorophores, an absorption and/or emission maximum of 650 - 1000 nm, in particular 700 - 900 nm (near-infrared fluores- - structures which biosynthetically form organic cence). chromophores or fluorophores, [0030] Chromophores or fluorophores with visible flu- 30 orescence are NBD, fluoresceins, rhodamines, tetrapy- - structures with high absorption cross section for X- rroles (e.g. porphyrines, protoporphyrine SX), pyrilium rays, dyes, Thai pyrilium dyes, croconium dyes, squarylium dyes, benzophenoxazinium dyes, benzothiaphenothi- - structures having an effect on electric impedance. azinium dyes, anthraquinones, naphthoquinones, 35 phthaloylacridones, azodyes, diazo dyes and complexes [0025] Subject matter of the invention is the use of EC- of the lanthanoid metals La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, CM containing paramagnetic metal ions. Preferred par- Tb, Dy, Ho, Er, Tm, Yb, and Lu, Eu, Tb, Yb with macro- amagnetic metal ions are ions of transitional metals and cyclic or open-chain polyaminocarboxylic acids or lanthanoid metals (e.g. metals having the atomic num- polyaminocarboxylic acids phosphoric acids. Fluores- bers 6-9, 21-29, 42, 43, 44, or 57-71), in particular ions 40 cein is particularly preferred. of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, [0031] Chromophores or fluorophores with near-infra- Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu. Mn, Cr, Fe, Gd and red fluorescence are polymethin dyes, particularly cya- Dy are preferred. Gd is particularly preferred. nine dyes, merocyanines, phthalocyanines, naphthalo- [0026] These ions are stably bound or complexed by cyanines, triphenylmethines, croconium dyes, complex forming structures or groups of chelators. The 45 squarylium dyes. Indocyanines, in particular indocyanine latter are macro-cyclic or open-chain polyaminocarbox- green, DODCI, DTDCI, DOTCI and DDTCI and deriva- ylic acids. Macro-cyclic chelator groups are preferably tives are preferred. Indocyanine green (ICG, Cardi- tetraazacyclododecane chelators, such as 1,4,7,1 0- oGreen, IC Green, DiagnoGreen) is particularly pre- tetraazacyclododecane-N,N’,N",N"’-tetraacetic acid ferred. (DOTA); 1,4,7,10-tetraazacyclododecan-N,N’,N"-triace- 50 [0032] Examples can be found in "Topics in Applied tic acid (DO3A); 1-Oxa-4,7,10-triazacyclododecane- Chemistry: Infrared absorbing dyes" Ed. M. Matsuoka, N,N’,N"-tretraacetic acid (OTTA); trans(1,2)-cyclohexan- Plenum, N.Y. 1990, "Topics in Applied Chemistry: The odiethylentriamine pentaacetic acid (CDTPA) and ana- Chemistry and Application of Dyes", Waring et al., Ple- logues thereof, or ethylenamine chelator groups, such num, N.Y., 1990, "Handbook of Fluorescent Probes and as N,N,N’,N",N"-diethylenetriamine pentaacetic acid55 Research Chemicals" Haugland, Molecular Probes Inc, (DTPA), ethylenediamine tetraacetic acid (EDTA), as 1996, DE-A-4445065, DE-A-4326466, JP-A-3/228046, well as their chemical substitution derivatives at the eth- Narayanan et al., J. Org. Chem. 60: 2391-2395 (1995), ylene and/or acetic acid residues. Further derivatives are Lipowska et al., Heterocyclic Comm. 1: 427-430 (1995),

6 11 EP 2 907 526 A1 12

Fabian et al., Chem. Rev. 92: 1197 (1992), WO96/23525, id, N,N-Di-(2-hydroxyethyl)glycine, ethylenebis-(hydrox- Strekowska et al., J. Org. Chem. 57: 4578-4580 (1992), yphenylglycine) and derivatives thereof by chemical sub- WO (Axis) and WO96/17628. stitution at the ethylene and/or acetic acid residues. Fur- [0033] Subject matter of the invention are also ECCM ther derivatives are DTPA-BMA, DPDP, TMT and comprising particulate or vesicular polymers which con- 5 HPDO3A. tain,transport and/or release air or fluorinatedgases (e.g. [0040] Moreover, chelate structures are selected from SFe or perfluorinated alkanes with 1-6 C-atoms or other the substance classes of polyphospates, such as sodium gases as described in WO97/29783). Echovist®, Levo- polyphosphate and hexametaphosphoric acid; vist, Sonavist®, Sonuvue and Optison® are particularly [0041] 1,3-diketones, e.g. acetylacetone, trifluoracety- appropriate. 10 lacetone, thenoyltrifluoroacetone; hydroxycarboxyic [0034] Subject matter of the invention are ECCM con- acids , e.g. lactic acid, citric acid, gluconic acid and 5- taining radionuclides. Radionuclides are non-metal nu- sulfosalicylic acid, polyamines, e.g. ethylenediamine, di- clides as well as metal nuclides for the techniques of ethylenetriamine, triethylenetetraamine, triaminotriethyl- SPECT (single photon emission computed tomography) amine; amino alcohols, e.g. triethanolamine and N-(2- or PET (positron emission tomography), respectively. 15 hydroxyethyl)-ethylenediamine; aromatic heterocyclic [0035] Non-metal nuclides are covalently bound to car- bases, e.g. 2,2’-diimidazole, picolinamine, dipicol- bons of chemical structures. A particularly preferred non- inamine, 1,10-phenanthrolin; phenols, e.g. salicylalde- metal nuclide is radioactive iodine (SPECT:125 I, 123I, hyde, disulfopyrocatechol; aminophenols, e.g. 8-hydrox- 131 124 11 I1 PET: I) or carbon C (PET). yquinoline oximesuifonic acid; oximes, e.g. dimethylgly- [0036] Metal radionuclides are preferably 90Y, 99mTc, 20 oxime, salicylaldoxime; peptides with chelating end 111Sn, 47Sc, 67Ga, 51Cr, 177mSn, 67Cu, 167Tm, 97Ru, groups, e.g. polycystein, polyhistidine, polyasparaginic 188Re, 177Lu, 199Au, 203Pb and 141Ce (for SPECT) and acid, polyglutamine acid, glycine-glycine-cystein or com- 86Y, 94mTc, 11OmIn, 68Ga, s4Cu (for PET). These are binations of such amino acids; Schiff’s bases, e.g. disal- bound by complex forming structures or radioactive che- icylaldehyde, 1,2-propylendiimine; tetrapyrroles, e.g. lators. 25 porphyrins, tetraphenylporphyrins, benzoporphyrins, [0037] Chelators for metal radionuclides are structures chlorines, tetraphenylchlorines, benzochlorines, bacteri- with donor atoms, such as N, S, O, which bind the metals ochlorines, pheophorbides; purpurinimides, expanded in appropriate configuration in space and form a cyclical tetra-and pentapyrroles (texaphyrines); sulphur com- metal complex or chelates. These are in particular IN 3S, pounds, e.g. toluene-dithiole, meso-2,3-dimercaptosuc- 30 N2S2 systems on the basis of aminoalkyl, thioalkyl, ami- cinic acid, dimercaptopropanol, thioglycolic acid, sodium nocarbonyl, thiocarbonyl structure elements (Kirk-Oth- diethyldithiocarbamate, dithizone, diethyldithiophos- mer Encyclopedia of Chemical Technology, Vol. 5, phoric acid, thiourea; phosphonic acids, e.g. nitrilotri- 339-368). methylene phophonic acid, ethylene diaminetetra(meth- [0038] Chelators on the basis of N3S and N2S2 are ylene phosphonic acid), hydroxyethylidendiphosphonic described e.g. in U.S. patents 4,444,690; 4,670,545;35 acid or combinations of 2 or more of the structures men- 4,673,562; 4,897,255; 4,965,392; 4,980,147; 4,988,496; tioned. 5,021,556 and 5,075,099, WO92/08494. Furthermore, [0042] Complex forming substances for 99mTc are, fur- 99m + 99m representative chelators are described in U.S. Pat. No. thermore, Tc(I)(H2O)3(CO)3 , from which the Tc- 5,559,214 A, WO 95/26754, WO 94/08624, WOtricarbonyl complex with amino carboxylic acids or other 94/09056, WO 94/29333, WO 94/08624, WO 94/08629 40 chelating donor atoms is formed. AI, WO 94/13327 A1 and WO 94/12216 [0043] A1; Subject matter of the invention are ECCM which WO89/00557, U.S. patents 4,647,447; 5,367,080; exhibit X-ray absorption, in particular triiodized aromatic 5,364,613. Chelates are also modified proteins which hydrocarbons and complexes with lanthanoid ions La, bind e.g. 99mTc (U.S. patent 5,078,985). Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and [0039] Chelate structures are selected from mycrocy- 45 Lu, Eu, Tb, Yb, preferably Gd, Tb, Dy, Ho, and structures clic or open-chain amino carboxylic acids. Macrocyclic containing triiodized aromatic hydrocarbons and com- chelator groups are preferably tetraazacyclododecane plexes with tanthanoid ions and iodixanol (Visipaque®), chelators, such as 1,4,7,10-Tetraazacyciododecane- iopromid (Uitravist®), ioxaglinic acid (Hexabrix®), iome- N,N’,N",N"’-tetraacetic acid (DOTA); 1,4,7,10-tetraaza- prol (Imeron®), iopamidol, iotrolan (Isovist), iosurcal (Me- cyclododecane-N,N’,N"-triacetic acid (DO3A); 1-Oxa- 50 litrast), iohexol (Omnipaque®), amidotrizoic acid (Peri- 4,7,10-triazacyclododecane-N,N’,N"-triacetic acid (OT- trast), meglumine ioxithalamate (Telebrix), iobitridoi ® TA) and dibenzo[18]crown-6, (CH 3)6-[14]-4,11]-dien-N4, (Xenetix ) and gadolinium-DTPA. and (2.2.2-cryptate). Open-chain amino carboxylic acids [0044] lodixanol (Visipaque®), iopromid (Ultravist®), are, for example, trans(1,2)-cyclohexanodiethylentri- ioxaglinic acid (Hexabrix®), iomeproi (imeron®), iopami- amine pentaacetic acid (CDTPA) and analogues thereof, 55 doi, iotrolan (Isovist), iosurcal (Melitrast), iohexol (Omni- N,N,N’,N",N"-diethyientriamine pentaacetic acid (DT- paque®), amidotrizoic acid (Peritrast), meglumine ioxith- PA), ethylene diamine tetraacetic acid (EDTA), N-(2-hy- alamate (Teiebrix), iobitridol (Xenetix ®), and gadolinium- droxy)-ethylene-diamine triacetic acid, nitrilotriacetic ac- DTPA are preferred.

7 13 EP 2 907 526 A1 14

[0045] In a particularly preferred embodiment, the EC- - gas-filled, polymeric microparticles or -vesicles, CM is gadolinium DTPA. [0046] The lesion-specific contrast agents (LSCM) ac- - gas precursors, cording to the invention are signalling or signal-modulat- ing substances for image synthesis procedures charac- 5 - organic, metal-organic or inorganic chromophores terised in that they interact with structures in the organism and fluorophores, or they are modified by structures in the organism as to their signalling properties and they provide additional im- - structures biosynthetically forming organic chromo- aging information which improve the specificity of the phores or fluorophores, method. Said additional information can be information 10 as to anatomy, morphology, function, metabolism or mo- - structures with high absorption cross section for X- lecular expression of specific factors. The substances rays, according to the invention are characterised in that after application in the lesion tissue they concentrate contin- - structures influencing electric impedance. uously and, in contrast to ECCM, remain in the lesion 15 over a longer period of time during examination and do [0050] Use of LSCM containing paramagnetic metal not exhibit any wash-in/wash-out phenomenon. The con- ions are subject matter of the invention. Preferred para- centration can be achieved by different mechanisms magnetic metal ions are ions of the transmission and which aim at preventing fast elimination from the blood lanthanoid metals (e.g. metals of atom numbers 6-9, circulation. The lesion-specific agents according to the 20 21-29, 42, 43, 44, or 57-71), in particular ions of Cr, V, invention can bind to specific binding sites, concentrate Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, in cell membranes, be activated by enzyme activity, bind Dy, Ho, Er, Tm, Yb and Lu. Mn, Cr, Fe, Gd and Dy are to extracellular proteins, absorbed by cells of the RES or preferred. Gd is particularly preferred. enter cells of the lesion tissue. These substances are [0051] These ions are stably bound or complexed by characterised in that their elimination from the blood cir- 25 complex forming structures or chelator groups. The latter culation takes clearly more time in comparison to the EC- are polyaminocarboxylic acids with macrocyclic or open- CM. Due to said longer period of time, the agents are chain structure. Groups of macrocyclic chelator agents capable of accumulating in the suspect lesions by the are preferably tetraazacyclododecane chelates, such as mechanisms mentioned and stay there. Preferably after 1,4,7,10-tetraazacyclododecane-N,N’,N",N"’-tetraace- 15 minutes to 24 hours, particularly preferred after 15 30 tic acid (DOTA); 1,4,7,1 0-tetraazacyclododecan- minutes to 3 hours, the process leads to demarcation of N,N’,N"-triacetic acid (DO3A); 1-Oxa-4,7,10-triazacy- the disease lesion from the surrounding healthy tissue, clododecane-N,N’,N"-triacetic acid (OTTA); which can be diagnostically measured. With this demar- trans(1,2)-cyclohexanodiethylentriamine pentaacetic cation which can be measured diagnostically, it is of no acid (CDTPA) and analogues thereof, or ethylenamine importance whether the LSCM concentrates in the tissue 35 chelator groups, such as N,N,N’,N",N"-diethylenetri- of the disease lesion or in the surrounding healthy tissue. amine pentaacetic acid (DTPA), ethylenediamine [0047] Preferably, the LSCM accumulates in the lesion tetraacetic acid (EDTA), as well as their derivatives by after 10 minutes and stays there for at least one hour, chemical substitution at the ethylene and/or acetic acid whereas particularly preferred the concentration of the residues. Further derivatives are DTPA-BMA, DPDP, LSCM in the lesion continuously increases within the pe- 40 TMT and HPDO3A. riod of 10 minutes to 60 minutes. [0052] Gadofosveset (Vasovist®), Gadofluorine, Gad- [0048] LSCM according to the invention are contrast- ofluorine-M and Gadomer-17 are particularly preferred. ing agents for the MRI, for X-ray-based techniques such [0053] LSCM containing superparamagnetic iron ox- as e.g. CT, for optical techniques, for optoaccoustic tech- ide particles are subject matter of the invention. These niques, for ultrasonic techniques and for nuclear medi- 45 are biocompatible and acceptable due to their stabilising cine techniques. protective coatings. Specifically, the iron oxide particles [0049] The LSCM are active substances, contrasting with protective coating have a diameter of 20 to 500 nm, agents or effector molecules, selected from the following preferably 20-200 nm. Protective coatings consist of pol- group, comprising: ymers, in particular polysaccharides such as dextran. 50 [0054] SPIOs, USPIOs, MIONs, Ferucarbutran (Res- - metal complexes with paramagnetic metals, ovist®, Supravist®) are particularly preferred. [0055] LSCM containing chromophores or fluoro- - superparamagnetic, ferromagnetic or ferrimagnetic phores are subject matter of the invention. Chromo- iron oxide particles with polymeric protective coat- phores or fluorophores are structures with an elaborate ings, 55 system of delocalised electrons, which absorb and fluo- resce within the spectral region of 300 to 1400 nm. - complex-bound, chelator-bound and covalently Chromophores or fluorophores with an absorption and/or bound radionuclides, emission maximum of 400 to 600 nm (visible fluores-

8 15 EP 2 907 526 A1 16 cence) as well as an absorption and/or emission maxi- 86Y, 94mTc, 11OmIn, 68Ga, 64Cu (for PET). These are mum of 650 to 1000 nm, in particular 700 to 900 nm (near- bound by complex forming substances or radiochelators. infrared fluorescence) are preferred. [0063] Chelators for metal nuclides are structures with [0056] Chromophores or fluorophores with visible flu- donor atoms such as N, S, O, which bind metals in an orescence are NBD, Fluorescein, rhodamines, tetrapyr- 5 appropriate spatial arrangement and form a cyclic metal roles (e.g. porphyrins, protoporphyrin IX), pyrilium dyes, complex or chelates. These are, in particular, N 3S, N2S2 thaipyrilium dyes, croconium dyes, squarilium dyes, ben- systems on the basis of aminoalkyl, thioalkyl, aminocar- zophenoxazinium dyes, benzothiaphenothiazinium bonyl, thiocarbonyl structure elements (Kirk-Othmer En- dyes, anthraquinones, napthoquinones, phthaloylacri- cyclopedia of Chemical Technology, Vol. 5, 339-368). 10 dones, azo dyes, diazo dyes, as well as complexes of [0064] Chelates on the basis of N 3S and N2S2 are de- the lanthanoide metals La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, scribed, for example, in U.S. patents 4,444,690; Tb, Dy, Ho, Er, Tm, Yb, and Lu, Eu, Tb, Yb with macro- 4,670,545; 4,673,562; 4,897,255; 4,965,392; 4,980,147; cyclic or open-chain polyaminocarboxylic acid or 4,988,496; 5 5,021 ,556 and 5,075,099, WO92/08494. polyaminocarboxylic acids phosphoric acids. Representative chelators are further described in U.S. [0057] Chromophores or fluorophores with near-infra- 15 patent no. 5,559,214 A, WO 95/26754, WO 94/08624, red fluorescence are polymethin dyes, in particular cy- WO 94/09056, WO 94/29333, WO 94/08624, WO anin dyes, merocyanins, phthalocyanins, naphthalocy- 94/08629 AI, WO 94/13327 A1 and WO 94/12216 A1 ; anins, triphenyl-methins, croconium dyes, squarilium WO89/00557, U.S. patents 4,647,447; 5,367,080; dyes. Examples can be found in "Topics in Applied 5,364,613. Chelates are also modified proteins binding Chemistry: Infrared absorbing dyes", Ed. M. Matsuoka, 20 e.g. 99mTc (U.S. patent 5,078,985). Plenum, N.Y. 1990, "Topics in Applied Chemistry: The [0065] Chelate structures are selected from macrocy- Chemistry and Application of Dyes", Waring et al., Ple- clic or open-chain aminocarboxylic acids. Macrocyclic num, N.Y., 1990, "Handbook of Fluorescent Probes and chelator groups are preferably tetraazacyclododecane Research Chemicals", Haugland, Molecular Probes Inc, chelates, such as 1,4,7,10-tetraazacyclododecane- 1996, DE-A-4445065, DE-A-4326466, JP-A-3/228046, 25 N,N’,N",N"’-tetraacetic acid (DOTA); 1,4,7,10-tetraaza- Narayanan et al., J. Org. Chem. 60: 2391-2395 (1995). cyclododecan-N,N’,N"-triacetic-acid (DO3A); 1-Oxa- Lipowska et al., Heterocyclic Comm. 1: 427-430 (1995), 4,7,10-triazacyclododecane-N,N’,N"-triacetic acid (OT- Fabian et al., Chem. Rev. 92: 1197 (1992), WO96/23525, TA) as well as dibenzo[18]crown-6, (CH 3)6-[14]-4,11]-di- Strekowska et al., J. Org. Chem. 57: 4578-4580 (1992), en-N4, and (2.2.2-cryptate). Open-chain amino carbox- WO (Axis) and WO96/17628, Chromophores with target- 30 yiic acids are, for example, trans(1,2)-cyclohexano-dieth- ing properties are preferred. Targeting properties of ylentriamine pentaacetic acid (CDTPA) and analogues chromophores can be achieved by conjugation of thereof, N,N,N’,N",N"-diethylenetriamine pentaacetic ac- chromophores to targeting molecules such as peptides, id (DTPA), ethylenediamine tetraacetic acid (EDTA), antibodies or other synthetic proteins. N-(2-hydroxy)-ethylenediamine triacetic acid, nitrilo [0058] The use of active substances biosynthentically 35 triacetic acid, N,N-di-(2-hydroxyethyl)-glycine, ethylen- forming chromophores or fluorophores after administra- bis-(hydroxyphenylglycine) as well as their derivatives tion of the active substances is subject matter of the in- by chemical substitution at the ethylene and/or acetic ac- vention. 5-aminolaevulin acid (5-ALA) and ester of 5-ALA id residues. Further derivatives are DTPA-BMA, DPDP, are mentioned to be preferred. TMT and HPDO3A. [0059] LSCM consisting of particulate or vesicular pol- 40 [0066] Furthermore, chelate structures are selected ymers containing, transporting and releasing air or fluor- from the substance classes of the polyphosphates, such inated gases (e.g. SF6 or perfluorinated alkanes with 1-6 as e.g. sodiumtripolyphosphate and hexametaphosphor- atoms or other gases as described in WO97/29783) are ic acid; 1,3-diketones, e.g. acetyl acetone, trifluoracetyl subject matter of the invention. Particulate polymers acetone, thenoyltrifiuoracetone; hydroxy carbonic acid, coupied to target-searching peptides or protein are par- 45 e.g. lactic acid, citric acid, gluconic acid, and 5-sufosalicyl ticularly preferred. acid; polyamines, e.g. ethylenediamine, diethylentri- [0060] LSCM containing radionuclides are subject amine, triethylentetraamine, triaminotriethylamine; ami- matterof the invention. Radionuclides are bothnon-metal noalcohols, e.g. triethanolamine and N-(2-hydroxye- nuclides and metal nuclides, each for SPECT (single thyl)-ethylendiamine; aromatic heterocyclic bases, e.g. photon emission computed tomography) or PET (posi- 50 2,2’-diimidazol, picolinamine, dipicolinamine, 1,10-phen- tron emission tomography) technique. anthrolin; phenols, e.g. salicylaldehyde, disulfopyrocate- [0061] Non-metal nuclides are covalently bound to car- chol; aminophenoles, e.g. 8-hydroxychinolin oxime sul- bons of chemical structures. A particularly preferred non- fonic acid; oximes, e.g. dimethylglyoxime, salicylaldoxi- metal nuclide is radioactive iodine (SPECT:125 I, 123I, me; peptide with chelating end groups, e.g. polycystein, 131I; PET: 124I) or carbon 11C (PET). 55 polyhistidine, polyasparagine acid, polyglutamine acid, [0062] Metal radionuclides are preferably 90Y, 99mTc, glycine- glycine-cysteine, or combinations of amino acids 111In, 47Sc, 67Ga, 51Cr, 177mSn, 67Cu, 167Tm, 97Ru, of that kind; Schiff’s bases, e.g. disalicylaldehyde, 1,2- 188Re, 177Lu, 199Au, 203Pb and 141Ce (for SPECT) and Propylendiime; tetra pyrrole, e.g. porphyrins, tetraphe-

9 17 EP 2 907 526 A1 18 nylporphyrines, benzoporphyrins, chlorines, tetraphe- are unsuitable for the synthetic imaging of the ECCM, nylchlorins, benzochlorins, bacteriochlorins, pheophor- since an increase of the spatial resolution leads to a sig- bides; purpurinimides, expanded tetra- and pentapyr- nificant increase of the measuring time and a reduction roles (texaphyrins); sulphur compounds, e.g. toluendithi- of the ratio of signal and noise. Furthermore, high-reso- ol, Meto-2,3- dimercaptosuccinic acid, dimercaptopropa- 5 lution measuring methods are unsuitable for obtaining nol, sodium diethyldithiocarbamate, dithizone, diethyl- rapid changes in the distribution of the contrast agent, dithiophosphoric acid, thiourea; phosphonic acids, e.g. as necessary for the rapid distribution of ECCM. nitrilotrimethylenphosphonic acid), ethylenediamine-tet- [0074] The individual components of the combination ra(methylenephosphonic acid), hydroxyethyliden di- of ECCM and LSCM according to the invention can be phosphonic acid, or combinations of 2 or more of the10 imaging contrasting agents or signalling substances for structures mentioned. synthetic imaging methods (monomodal) or multiple (pol- [0067] Complex forming structures for 99mTc are fur- ymodal, multimodal) imaging methods. 99m + 99m thermore Tc(I)(H2O)3(CO)3 from which the Tc tri- [0075] The monomodal methods can be selected from carbonyl complex with amino carbonic acids or other the group comprising: MRT, PET, CT, optical imaging, chelating donor atoms is formed. 15 ultrasound, SPECT, X-ray. [0068] Chelator structures and complex forming sub- [0076] Synthetic imaging methods which are appropri- stances are bound to carrier, vector, targeting or trans- ate for the illustration of combinations of ECCM and LS- porter molecules such as e.g. polymers, proteins, pep- CM are fusion methods of different imaging methods tides, antibodies, oligonucleotides, polysaccharides and such as PET-CT, PET-MRI, PET-optical imaging, MRI- 20 combinations and derivatives thereof, via linkers. In this CT1 ultrasound optical imaging, PET-SPECT, SPECT- context, chelator structures and complex forming sub- CT, MRT-optical imaging and SPECT-MRT. stances are linked by means of functional groups of the [0077] For the use of a combination according to the chelator backbone, by means of derivatisation of donor invention, which is illustrated by means of polymodal groups into derivatised donor groups such as e.g. acids methods, devices and software are used which visualise into amides, alcohols into ethers, thioles into thioethers, 25 the signals of the individual components separately as or by means of free coordination sites of the metal. The to space and time and which carry out an automatic com- coupling to carrier, vector, targeting or transporter mol- parison of the spatial and temporal signal intensities for ecules can take place in molar ratios of 1 to 100. Linker each suspect lesion or suspect area. and derivatives for chelators are described [0078] in With monomodal application of the combination WO94/08629, WO94/09056, WO96/20754. 30 of the invention, first, for example, the ECCM is applied [0069] Preferred structures are99m Tc-Medronat, and then, following with a time delay, the LSCM is ap- 99mTc-Sestamibi, 99mTc-ECD, 99mTc-MAG3, 111In-DT- plied. The time interval between the application of the PY-octreotide, 111In-DTPA-octreotate, 18F-fluordesoxy- ECCM and the LSCM is determined in such a way that glucose (FDG), 18F-dopamine, 18F-L-DOPA, 18F-fluor- the application of LSCM only takes place when the blood choline, 18F-fluormethylethylcholin, 18F-fluordihydro- 35 level of ECCM has sunk to a low level and no longer testosterone, 68Ga-NODAGATOC, 68Ga-DOTYTOC. interferes with the subsequent application of the LSCM. [0070] LSCM exhibiting an absorption of X-rays are In that way, the signals of the imaging agents cannot subjectmatter ofthe invention,in particular triiodated aro- overlap and influence each other. Since the ECCM has ma substances and complexes with lanthanoid ions La, fallen to such low level only ten minutes after application, Ce, 40 the subsequent application must be carried out with a [0071] Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, delay. Yb, and Lu, Eu, Tb, Yb, preferably Gd, Tb, Dy, Ho, as [0079] In case the combination of ECCM and LSCM well as structures containing the triiodated aroma sub- according to the invention are visualised by means of stances and complexes with lanthanoid ions. polymodal synthetic imaging, the ECCM and the LSCM [0072] A particular advantage of the combination of 45 can also be applied simultanously or with a very small ECCM and LSCM according to the invention is the pos- delay. By using different synthetic 15 imaging methods, sibility of using high-resolution imaging. With use of EC- overlap of the individual signalling components is avoid- CM alone, the use of high-resolution imaging was not ed. The signalling components of the ECCM and the LS- possible, since the measure intervals available are very CM can be visualised separately. The almost simultane- short. However, the combination of ECCM and LSCM 50 ous application is appropriate, above all, if radioisotopes according to the invention makes it possible to use high- with a short decay time are used. This applies, e.g. if 18F- resolution imaging to obtain specific morphological infor- based PET tracer are combined with the MRI ECCM Gd- mation. DTPA. [0073] During any imaging methods, the assessment [0080] Thus, the combination of ECCM and LSCM is of exact morphological details depends on a high spatial 55 the subject matter of the present invention when used as: resolution, in order to obtain high-resolution images, however, a longer examination period is necessary. - monomodal time-delayed application, e.g. monomo- Moreover, measuring methods have to be applied which dal measurement 0-15 minutes after injection of the

10 19 EP 2 907 526 A1 20

ECCM and second measurement 15 minutes to 24 either the ECCM or the LSCM can be administered hours after injection of the LSCM first. - polymodal time-delayed application - polymodal simultaneous application 4. The extracellular contrast agent (ECCM) for the 5 diagnosis of lesions according to claim 1 or 2, where- [0081] The time-delayed application of the individual in, in the case of the polymodal method either components of the combination can be achieved by dif- ferent devices. The combination according to the inven- a. the ECCM and the LSCM are to be adminis- tion can be carried out by two-chamber or multiple-cham- tered consecutively; or ber syringes or cartridges. A further device for the ad- 10 ministration of the combination according to the invention b. the ECCM and the LSCM are to be adminis- is a device for carrying out the time-controlled application tered simultaneously. of the individual components. Hereby, the time control is carried out in correspondence with the application regi- 5. The extracellular contrast agent (ECCM) for the men for the LSCM and ECCM as described for the meth- 15 diagnosis of lesions in combination/conjunction with od of the present invention. a lesion-specific contrast agent (LSCM) according [0082] Thus, subject matter of the present invention is to any one of claims 1 to 4, wherein the ECCM and an application device for the combined application of an the LSCM are to be administered with a time delay extracellular contrast agent (ECCM) for the diagnosis of of at least 10 to 15 minutes. lesions in combination with a lesion-specific contrast20 agent (LSCM), wherein the application device has at 6. The extracellular contrast agent (ECCM) for the least two chambers or receptacles for the separate ab- diagnosis of lesions in combination conjunction with sorption and application of the ECCM and the LSCM. a lesion-specific contrast agent (LSCM) according [0083] Said application device can be a two-chamber to any one af claims 1 to 5, wherein the ECCM is or multiple-chamber syringe, it can also be a two-cham- 25 gadolinium-DTPA. ber or multiple-chamber cartridge. Furthermore, an ap- paratus comprising two distinct chambers containing an 7. The extracellular contrast agent (ECCM) for the LSCM and an ECCM, respectively, wherein the release diagnosis of lesions in combination/conjunction with of contrast agent is controlled with an individual pump a lesion-specific contrast agent (LSCM) according for each chamber, and wherein the outlets of the two30 to any one of claims 1 to 6, wherein the LSCM is chambers are fitted with tubing which is connected by a enriched inthe lesionafter 10 minutesand is retained Y-piece which ends in a single tube so that both contrast there for at least I hour. agents are applied to the patient via this single tube may be used as application device. 8. The extracellular contrast agent (ECCM) for the [0084] Furthermore, an embodiment of the present in- 35 diagnosis of lesions in combination/conjunction with vention is the use of an application device for the admin- a lesion specific contrast agent (LSCM) according istration of an LSCM and an ECCM to a subject or patient, to any one of claims 1 to 7, wherein the imaging whereby the application regimen for the LSCM and EC- signals are immediately interpolated. CM is as described for the method of the present inven- tion. 40 9. An application device for the combined application [0085] Further embodiments of the invention are as of an extracellular contrast agent (ECCM) for the di- follows: agnosis of lesions in combination/conjunction with a lesion-specific contrast agent (LSCM), wherein said 1. An extracellular contrast agent (ECCM) for the application device allows separate recording and ap- diagnosis of lesions in combination/conjunction with 45 plication of the ECCM and the LSCM. a lesion-specific contrast agent (LSCM). 10. The application device according to claim 9, 2. The extracellular contrast agent (ECCM) for the wherein said application device has at least two diagnosis of lesions according to claim 1, wherein chambers or receptacles for separate recording and the individual contrast agents of the combination of 50 application of the ECCM and the LSCM. ECCM and LSCM are imaging contrast agents for a synthetic imaging method (monomodal) or multiple 11. A method for the diagnosis of lesions, wherein synthetic imaging methods (polymodal). an extracellular contrast agent (ECCM) is adminis- tered in combination/conjunction with a lesion-spe- 3. The extracellular contrast agent (ECCM) for the 55 cific contrast agent and, preferably, the interpolation diagnosis of lesions according to claim 1 or 2, where- of the imaging signals occurs immediately. in, in the case of the monomodal method, ECCM and LSCM are to be administered consecutively, wherein

11 21 EP 2 907 526 A1 22

EXAMPLES: Example 3:

Example 1: [0091] A patient, typically in his late 50s or early 60s with a history of a recent heart attack is now being inves- [0086] A middle-aged patient. This patient suffered 5 tigated for viable myocardium before cardiac bypass sur- from a malignant brain tumour, a glioblastoma, and was gery. The patient’s history includes a low grade nicotine treated for it. Apart from an operation, the treatment also abuse 20 years ago with overall eight pack-years expo- included radiotherapy of the brain with increased radia- sure and a history of tuberculosis during adolescence. tion in the former operation area using directed stereo- Previous diagnostic coronary angiography has revealed tactic techniques. After about six months, the patient’s 10 stenoses in the coronary arteries. PET imaging with use initially good clinical situation deteriorated. The clinical of F18 - FDG as radiotracer revealed viable myocardium examination results in presumed tumour growth recur- with the possibility to improve cardiac function with a ring. revascularization procedure. Coincidentally an in- [0087] Diagnostic imaging by means of a PET-CT de- creased tracer uptake was seen during cardiac PET im- vice combination can illustrate tumours both by using X- 15 aging in the left upper lobe of the lung, being consistent ray contrast agents and by using PET isotopes. With an with cancer or infectious disease. extracellular CT contrast agent such as e.g. Ultravist ® a [0092] A targeted contrast enhanced high-resolution region accumulating contrast agent inhomogeneously in thin slice computed tomography scan was performed in the region of the former tumour bed can be seen. With the upper lung lobes showing a well enhancing, approx- regard to differential diagnosis, apart from a tumour re- 20 imately 2 cm measuring lesion. The high resolution thin curring - a local relapse -, cell death caused by high ra- slice images clearly showed a solid appearance of the diation - radionecrosis - is possible. tumor and very thin streaky structures surrounding the [0088] The PET isotope 18F-fluordeoxyglucose (FDG) tumor in a radiate appearance, being typical for spiculae as LSCM, which was injected simultaneously, provides of a lung cancer. The combination of contrast enhance- the explanation for the differential diagnosis: the missing 25 ment in the solid lesion and the speculated appearance concentration of the LSCM in the cells of the region, of the tumor secured the diagnosis of a small lung cancer, which, in the CT, had shown a concentration of ECCM, proves the presence of radionecrosis. Further therapy consists in the administration of corticoids; the patient’s Claims prognosis is clearly better than in the case of a local re- 30 lapse being present. 1. An extracellular contrast medium (ECCM) for the use in the diagnosis of lesions, wherein the ECCM is se- Example 2: lected from the group comprising Gadobutrol (Gado- vist®), gadopentetatic, gadobenic acid (Multi- [0089] A patient, typically between 50 and 70 years of 35 hance®), gadodiamide (Omniscan), gadoxetic ac- age, is admitted to hospital for further diagnosis and ther- id/disodium salt (Primovist®; Gd-EOB-DTPA), and apy due to blood deposits in the stool. The coloscopy gadoteridol (Prohance®), wherein the ECCM is to be carried out showed a malign tumour of the colon. During used in combination with a lesion-specific contrast the ultrasound scan of the liver, which was also carried medium (LSCM), and wherein the LSCM is selected out, an individual, defined focus was found in the right 40 from the group comprising 99mTc-Medronat, 99mTc- hepatic lobe which lead to the presumption of a metas- Sestamibi, 99mTc-ECD, 99mTc-MAG3, 111ln-DTPY- tasis in the liver, a liver metastasis. octreotide, 111ln-DTPA-octreotate, 18F-fluordesoxy- [0090] The magnetoresonance tomography which glucose (FDG), 18F-dopamine, 18F-L-DOPA, 18F- was carried out, first, with an extracellular contrast agent fluorcholine, 18F-fluormethylethylcholin, 18F-fluordi- (EECM, e.g. Magnevist®), then directly followed by a le- 45 hydro-testosterone, 68Ga-NODAGATOC, 68Ga-DO- sion-specificcontrast agent (LSCM, e.g. Resovist ®), con- TYTOC, firmed, in the first step, the presence of a liver focus in and wherein the individual contrast agents of the the right hepatic lobe by means of ECCM. Differentiation combination of ECCM and LSCM are imaging con- of the type of tumour, however, is not possible. In this trast agentsto be usedin a multiplesynthetic imaging case, only the accumulation of the tumour with the LSCM 50 method (polymodal), wherein said synthetic imaging showed that the cells of this dimension are liver cells and method is a fusion method selected from the group not tumour cells. Thus, metastasis of the colon tumour comprising PET-MRI and SPECT-MRT -and where- could be excluded, the diagnosis of a benign simple he- in either mangioma of the liver could be secured by the combined contrast agents examination. The patient is subjected to 55 a. the ECCM and the LSCM are to be adminis- a normal tumour operation of the colon. tered consecutively; or b. the ECCM and the LSCM are to be adminis- tered simultaneously, and

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wherein the LSCM is enriched in the lesion after 10 minutes and is retained there for at least 1 hour, and wherein the imaging signals are immediately inter- polated. 5 2. The extracellular contrast medium (ECCM) for the use in the diagnosis of lesions to be used in combi- nation with a lesion-specific contrast medium (LS- CM) according to claim 1, wherein the ECCM and the LSCM are to be administered with a time delay 10 of at least 10 to 15 minutes.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

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