Compounds comprising a silicon-based fluoride acceptor group useful as radiopharmceutical compounds

Abstract

Provided are compounds of formula (IA) or formula (IB) or a salt thereof, wherein RT represents a targeting moiety which is capable of binding to a target of therapeutic and / or diagnostic interest; L1A and L1B each independently represents a divalent linking group, or is absent; L2A and L2B each independently represents a divalent linking group, or is absent; RCH represents (i) a chelating group or (ii) a chelate group comprising a complexed radioactive or non-radioactive metal cation. Compounds in accordance with the invention are useful as radiopharmaceuticals.

Description

[0001] Compounds Comprising a Silicon-Based Fluoride Acceptor Group useful as Radiopharmaceutical Compounds

[0002] Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. One of the intrinsic properties of neuroendocrine tumors (NETs) is the pathological overexpression of somatostatin receptors (SSTRs) that mediates reduced sensitivity to growth inhibitory factors (i.e., the endogenous ligands SST-14 and -18, respectively) and thus, provides the basis for imaging and therapy (peptide receptor radiotherapy (PRRT)) using radiolabeled SST analogs.1In particular, the somatostatin receptor 2 (sstR2) is frequently overexpressed on malignant tissue. The octapeptide DOTA-Tyr3-octreotate (DOTA-TATE), which is derived from SST, shows very high sst2 affinity, excellent pharmacokinetics, and is already used commercially for clinical imaging ([68Ga]Ga-DOTA-TATE) and therapy ([177Lu]Lu-DOTA-TATE).2-4

[0003] For imaging, positron emission tomography (PET) is of great importance to the field of nuclear medicine, since it can be used to detect and monitor biological and pathophysiological processes.5-8Currently, targeted68Ga-labeled radiotracers dominate PET imaging thanks to the clinical introduction of approved68Ge / 68Ga generators.9Thus, for example the success of FDA-approved kits such as NETSPOT® (Advanced Accelerator Applications kit formulation) for the preparation of the high-affinity somatostatin-targeted [68Ga]Ga-DOTA-TATE (TATE = (Tyr^-octreotate, DOTA = 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid) for NETs imaging, is pushing PET applications forward.10'13Despite the success of68Ga- labeled targeted tracers, increasing interest in switching from68Ga- to18F-labeled compounds, due to the beneficial properties of the fluorine-18 nuclide, has emerged in recent years.14'16In fact, due to the longer half-life (18F:110 min vs68Ga: 68 min), the delivery of fluorine-18 is feasible from cyclotrons thus, resulting in cost reduction. Moreover, the lower positron energy (Epmax(18F) = 634 keV vs Epmax(68Ga) = 1899 keV) and a higher positron decay yield (97% vs. 89%68Ga) enables the application of lower levels of activity and delayed imaging protocols, whilst maintaining better spatial resolution of PET images.17'20

[0004] Generally, electrophilic and nucleophilic fluorination can be used for18F-radiolabeling. The synthesis of [18F]FDG (FDG = fluorodeoxyglucose), which has been successfully used for PET imaging for over 40 years, was first carried via an electrophilic substitution reaction. However this reaction resulted in low radiochemical yields (RCY = 8%) and required a long reaction time (S2 h).21-24To obtain a fast and efficient method for18F-fluorination, research moved away from Carbon-18F bond formation and more towards alternative methods such as aluminum-, boron-, and silicon-18F bond formation, which can be generated via an nucleophilic fluorination.25-27Metal-F coordination-based methods (e.g. using AIF2+complexes) have some advantages, such as fast labelling (15 min) via an substitution reaction, but the reaction requires high temperatures (110°C) and results in lower radiochemical yields (RCYs) compared to isotopic exchange reactions (IE).28 29In contrast, the18F / 19F isotope exchange reaction used for both boron-, and silicon-18F bond formation takes place at milder reaction conditions (e.g. room temperature, aqueous medium), with the Si-18F bond formation being the most promising due to its superior reactions conditions (10 min, room temperature, RCYS50%).30-32Moreover, as a charged small ion, the unreacted fluoride-18 can be easily removed from the precursor by solid phase extraction (SPE).33-35

[0005] In 2005, the so-called Silicon Fluoride Acceptor (SiFA) method was established by Ting et al., with the formation of alkylfluorosilicates. It was then further optimized by Schirrmacher et al. with the introduction of two ferf-butyl groups for protection against hydrolysis, resulting in a high stability of the corresponding Si-18F bond.30’36 37In the last decades, several different SiFA building blocks, that share the same core structure and enable different conjugation methods have been developed and are frequently applied to biomolecules. For example, (SiFA)BA (4-(di-ferf-butylfluorosilyl)benzoic acid) (Fig. 1 , A) can be used for direct amide bond formation by coupling to peptidic structures.38However, their major drawback is the lipophilicity caused by the two terf-butyl groups and the aromatic system. Of note, these SiFA moieties, featuring only one anchoring group, can exclusively undergo terminal incorporation into a peptide sequence; this causes a significant increase of the lipophilicity of the respective radiotracers and therefore, can lead to unfavourable in vivo performance.37’39Previous approaches aiming at the reduction of lipophilicity focused on the introduction of hydrophilic building blocks, as successfully demonstrated by Schirrmacher et al. and resulted in the currently most promising fluorine-18 sstR2-addressing ligand [18F]SiFA / / n-TATE.40-43Specifically, an increased hydrophilic character is achieved with the incorporation of the permanently positively charged SiFA synthon SiFA / / n (N-(4-(di-ferf-butylfluorosilyl)benzyl)- N,N-dimethyl-4-oxobutan-1-aminium) (Fig. 1 , A), the use of polyethylene glycol-like linkers, polar charged amino acids and a carbohydrate component. Despite the encouraging results of [18F]SiFA / / n-TATE, this multicomponent strategy is synthetically significantly more complex and expensive compared to the gold standard [nat / 68Ga]Ga-DOTA-TATE, hampering the clinical establishment. To simplify this complex synthesis, but still benefiting from the excellent labelling properties of SiFAs, the development of less lipophilic SiFA building blocks remains of great interest.

[0006] With regard to the treatment of neuroendocrine tumors, [177Lu]Lu-DOTA-TATE (Lutathera®) was approved for therapeutic use by the EMA and the FDA and has since become the gold standard for radioligand therapy of neuroendocrine tumors.44Lutetium-177 is produced in a cyclotron and can be easily delivered in high activities because of its long half-life of 6.6 day which is also the ideal length for radio ligand therapy.44Additionally, the low fr maximal emission energy of 498 keV is in a preferred range for fr therapy.44Another benefit of lutetium-177 is the low abundance / -emission of 208 keV which allows for dosimetry calculations. Together with [nat / 68Ga]Ga-DOTA-TATE for imaging, this results in a therapeutic pair that is frequently used today in nuclear medicine for the treatment of neuroendocrine tumors. However, theranostic pairs such as [68Ga]Ga-DOTA-TATE and [177Lu]Lu-DOTA-TATE exhibit different chemical and pharmacological properties due to the different metals incorporated, which has increased interest in different strategies to attain radio-theranostic compounds in modern medicine.45 46

[0007] In this context, a promising new class of theranostic radiohybrids for prostate-specific membrane antigen (PSMA) targeting compounds has recently been developed by Wurzer et al ,9’47-49This concept includes a SiFA for18F-fluorination via an18F / 19F isotope exchange reaction and additionally a chelator for radiometallation (with68Ga or177Lu, among others). This results in a chemically identical pair of compounds (either19F / radiometal or18F / non- radioactive metal), which has identical pharmacokinetics and can be used for both diagnostic and therapeutic applications. A side benefit is the balancing of the high lipophilicity of the SiFA through the hydrophilic chelator. The radiohybrid ligand [18F]rhPSMA7.3 (POSLUMA®), which contains the SiFA building block (SiFA)BA for18F-labeling und a DOTA chelator, was recently approved by the FDA (Posluma®).50

[0008] To overcome the high lipophilicity of current SiFA building blocks the new bifunctional (SiFA)SeFe (3-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-5-(di-terf- butylfluorosilyl)benzoic acid) (Fig. 1 , B) was developed. The two linkers (carboxylic acid and amine) enable a bridged incorporation and allow for the design of linear peptides as (SiFA)SeFe is used as a regular amino acid. This should lead to a shielding of the lipophilicity by adjacent amino acids increasing the overall hydrophilicity of the ligand.

[0009] Based on the clinically most relevant sstR2-targeting octapeptide TATE for neuroendocrine tumors (NETs)51the (SiFA)SeFe containing rh-ligand (SiFA)SeFe-rhTATE4 was developed (Figure 2). As for previous reported rh-ligands, DOTA was chosen as representative chelator. The in vitro properties of the ligand, including binding affinity, lipophilicity, human albumin binding, as well as stability in human serum were assessed. The obtained in vitro results have been compared to the FDA approved benchmark [nat / 177Lu]Lu-DOTA-TATE, and the well- known18F-labeled SST-analogue for NETs [nat / 18F]SiFa / / n-TATE. Moreover, the biodistribution was investigated in vivo in AR42J tumor-bearing CD1-nu / nu mice after 1 h post injection (p.i.) for the18F-labeled compound and 1 h, 6 h and 24 h p.i. for the177Lu-labeled compound. In conclusion, the development of a somatostatin receptor targeted theranostic agent ((SiFA)SeFe-rhTATE4) could be achieved via the rh-concept using the hydrophilic bifunctional building block (SiFA)SeFe. Both, the labeling with flourine-18 and with lutetium-177 could be implemented quickly and efficiently with high RCYs and radiochemical purities (RCPs). [nat / 177Lu]Lu-(SiFA)SeFe-rhTATE4 showed high HSA binding, a comparable somatostatin receptor binding affinity to the references SiFA / / n-TATE and Lu-DOTA-TATE, as well as reduced lipophilicity compared to [18F]SiFA / / n-TATE. Notably, the use of (SiFA)SeFe can be implemented in a versatile fashion to bridge a metal chelator to different peptidic domains to achieve rh-compounds addressing different biological targets, such as PSMA, chemokine 4 receptor (CXCR4), GRPR (gastrin-releasing peptide receptor), integrins (e.g. as|3i, avp3, avPs, avPe), GLP-1 R (glucagon-like peptide-1 receptor), neurokinin-1 and CCK2 (cholecystokinin receptor 2). Another straightforward application could be the tethering of SeFe to blood brain barrier (BBB)-crossing peptides52to favor brain uptake of the radiotracer. Similarly, the tethering of fibroblast-activation-protein (FAP) inhibitors (FAPIs) to (SiFA)SeFe can also be achieved via well-established chemical strategies53to target FAP over-expressed in the stroma of epithelial tumors.

[0010] Data on the integration of (SiFA)SeFe in radiohybrid tracers targeted to CXCR4 (compound (SiFA)SeFe-rhCPCR4.1) and to GRPR receptors (compound (SiFA)SeFe-rhGRPRI) have been obtained, including in vitro data on lipophilicity and receptor binding affinity, which confirm the beneficial role of the new Si-F building block and demonstrate its broad applicability.

[0011] The following items summarize aspects of the invention, and the summary is further supplemented by the detailed description of the invention provided below.

[0012] 1 . A compound of formula (IA) or formula (IB) or a salt thereof: wherein

[0013] RTrepresents a targeting moiety which targets a structure of therapeutic and / or diagnostic interest;

[0014] L1Aand L1Beach independently represents a divalent linking group, or is absent;

[0015] L2Aand L2Beach independently represents a divalent linking group, or is absent;

[0016] RCHrepresents (i) a chelating group or (ii) a chelate group wherein the chelating group comprises a complexed radioactive or non-radioactive metal cation, and the fluorine atom F attached to the silicon atom Si in formula (IA) and in formula (IB) is independently selected from radioactive [18F]fluorine and non-radioactive [19F]fluorine.

[0017] 2. The compound or salt in accordance with item 1 , wherein RCHrepresents

[0018] (i) a chelating group which is provided by a chelating agent selected from the group consisting of diethylenetriaminepentamethylenephosphonic acid (EDTMP), diethylenetriaminepentaacetic acid (DTPA), bis(carboxymethyl)-1 ,4,8,11-tetraaza- bicyclo[6.6.2] hexadecane (CBTE2a), cyclohexyl-1 ,2-diaminetetraacetic acid (CDTA), 4- (1 ,4,8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N'-[5- [acetyl(hydroxy)amino]-,pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]- amino]pentyl]-N-hydroxybutandiamide (DFO), 1 ,4,7, 10- tetraazacyclododecane- 1 ,7-diacetic acid (DO2A), 1 ,4,7,10-tetraazacyclododecan-N,N',N",N"'-tetraacetic acid (DOTA), 2-[1 ,4,7,10- tetraazacyclododecane-4,7,10-triacetic acid]-pentanedioic acid (DOTAGA or DOTA-GA),

[0019] 1.4.7.10-tetrakis(carbamoylmethyl)-1 ,4,7,10-tetraazacyclododecane (DOTAM), N,N'- dipyridoxylethylendiamine-N,N'-diacetate-5,5'-bis(phosphat) (DPDP), ethylenediamine-N,N'- tetraacetic acid (EDTA), ethyleneglykol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1 ,4,7,10-tetraazacyclodecan-

[0020] 4.7.10-triacetate (HP-DOA3), 1 , 4, 7-triazacyclononan-1 -succinic acid-4, 7-diacetic acid

[0021] (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1 ,4,7-triazacyclononane

[0022] (NODAGA), 1 ,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1 ,4,8,11- tetraazabicyclo[6.6.2]hexadecane (TE2A), 1,4, 8,11-tetraazacyclododecane-1,4,8,11- tetra_,acetic acid (TETA), terpyridine-bis(methyleneamine) tetraacetic acid (TMT), 1,4,7,10- tetraazacyclotridecan-N,N',N",N"'-tetraacetic acid (TRITA), triethylenetetraaminehexaacetic acid (TTHA), N,N'-bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (H2macropa), 4- amino-4-{2-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-carbamoyl]-ethyl} heptanedioic acid bis-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1 ,4-dihydro-pyridin-2-ylmethyl)-amide] (THP), 1 ,4,7-triazacyclononane-1 ,4,7-tris[methylene(2-carboxyethyl)phosphinic acid (TRAP), 2-(4 , 7, 10-tris(2-amino-2-oxoethyl)-1 ,4,7, 10-tetraazacyclododecan-1-yl)acetic acid (DO3AM), 1 ,4,7,10-tetraazacyclododecane-1 ,4,7, 10-tetrakis[methylene(2-carboxyethylphosphinic acid)] (DOTPI), S-2-(4-isothiocyanatobenzyl)-1 ,4,7,10-tetraazacyclododecane tetraacetic acid, hydrazinonicotinic acid (HYNIC), 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]- eicosan-1,8-diamine (SarAr), 6-Amino-6-methylperhydro-1,4-diazepine-N,N,N',N'-tetraacetic acid (AAZTA), (6-pentanoic acid)-6-(amino)methyl-1,4-diazepine triacetate (DATA), pentadeca-1,4,7,10,13-penta-aminopentaacetic acid (PEPA), hexadeca-1,4,7,10,13,16- hexaamine-hexaacetic acid (HEHR), 4-{[bis(phosphonomethyl)) carbamoyl]methyl}-7,10-bis (carboxymethyl)-1 ,4,7,10-tetraazacyclododec-1-yl) acetic acid (BPAMD), N (4-{[bis (phosphonomethyl)) carbamoyl] methyl}-7,10-bis(carboxymethyl)-nona-1,4,7-triamine triacetic acid (BPAM), 1 ,2-[{6-(carboxylate) pyridin-2-yl} methylamine] ethane (DEDPA, H2DEDPA), deferoxamine (DFO), deferiprone, (4-acetylamino-4-yl) {2-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1,4- dihydro-pyridin-2-ylmethyl) -carbamoyl]-ethyl}-heptanedioic acid bis-[(3-hydroxy-1 ,6-dimethyl- 4-oxo-1 ,4-dihydro-pyridin-2-ylmethyl)-amide] (CP256), YM103, tetraazycyclodecane- phosphinic acid (TEAP), 6,6'-[{9-hydroxy-1 ,5-bis-(methoxycarbonyl)-2,4-di(pyridin-2-yl)-3,7- diazabicyclo[3.3.1]nonane-3,7-diyl}bis(methylene)]dipicolinic acid (H2bispa2), 1 ,2-[{6- (carboxylato)pyridin-2-yl}methylamino]-ethane (H2dedpa), N,N'-bis(6-carboxy-2- pyridylmethyl)-ethylenediamine-N,N'-diacetic acid (H4octapa), N,N'-bis(2-hydroxy-5- sulfonylbenzyl)-N,N'-bis-(2-methylpyridyl)ethylenediamine (HeSbbpen), triethylenetetramine- N,N,N,,N' N"',N"'-hexaacetic (TTHA), 2-aminomethylpiperidine triacetic acid (2-AMPTA), 2-(N- (2-Hydroxybenzyl)aminomethyl)piperidine (2-AMPTA-HB), 4-nitro-2-hydroxybenzyl-2-{[(6)- trans-2-[benzyl(carboxymethyl)amino] cyclohexyl] (carboxymethyl)amino}acetic acid (RESCA), and 6-carboxy-1 , 4, 8, 11 -tetraazaundecane (N4); or

[0023] (ii) a chelate group wherein any one of these chelating groups comprises a complexed radioactive or non-radioactive metal cation.

[0024] 3. The compound or salt in accordance with item 1 or 2, wherein RCHrepresents (i) a chelating group which is provided by a chelating agent selected from the group consisting of DOTA, DOTAGA, DOTAM, DO3AM, NOTA and NODAGA, more preferably from DOTA and DOTAGA, or (ii) a chelate group wherein any one of these chelating groups comprises a complexed radioactive or non-radioactive metal cation.

[0025] 4. The compound or salt in accordance with any of items 1 to 3, wherein the complexed metal cation is selected from cations of43Sc,44Sc,47Sc,51Cr,52mMn,55Co,57Co,58Co,52Fe, 227Th, and from cations of nonradioactive isotopes of any of these metals.

[0026] 5. The compound or salt in accordance with any of items 1 to 4, wherein the complexed metal cation is selected fromnatGa3+,68Ga3+,natLu3+,177Lu3+,90Y3+andnatY3+, more preferably fromnatGa3+,68Ga3+,natLu3+, and177Lu3+.

[0027] 6. The compound or salt in accordance with any of items 1 to 5, wherein RCHrepresents a chelating group of formula (CH-1) or a chelate group of any of formulae (CH-2) or (CH-3): wherein the waved line marks a bond which attaches the group to the remainder of the compound, the complexed Lu3+cation in formula (CH-2) is selected from a cation of non-radioactivenatLu and a cation of radioactive177Lu, and the complexed Ga3+cation is selected from a cation of non-radioactivenatGa and a cation of radioactive68Ga.

[0028] 7. The compound or salt in accordance with any one of items 1 to 6, wherein the targeting moiety RTrepresents a peptide moiety, preferably a peptide moiety which comprises 3 to 20 amino acid units, more preferably a peptide moiety which comprises 3 to 10 amino acid units.

[0029] 8. The compound or salt in accordance with item 7, wherein the peptide moiety RTrepresents a linear chain of amino acid units, or a peptide moiety comprising a cyclic peptide structure.

[0030] 9. The compound or salt in accordance with any one of items 1 to 8, wherein the targeting moiety RTrepresents a targeting moiety which targets a structure selected from the group consisting of a somatostatin receptor (SSTR), a gastrin releasing peptide receptor (GRPR), a C-X-C chemokine receptor type 4 (CXCR4), a glucagon-like peptide-1 receptor (GLP1 R), a cholecystokinin B receptor (CCKBR or CCK2), prostate specific membrane antigen (PSMA), fibroblast activation protein alpha (FAP), an integrin (such as as|3i,av|33, avPs, avPe), and neurokinin-1 , or is a blood brain barrier crossing peptide.

[0031] 10. The compound or salt in accordance with item 9, wherein the targeting moiety RTtargets a somatostatin receptor and can be derived from a receptor agonist or receptor antagonist selected from the group consisting of Tyr^Thr^-Octreotide (TATE); Tyr3-Octreotide (TOC); Thi^-Octreotide (ATE); 1-Nal3-Octreotide (NOC); 1-Nal3,Thr®-Octreotide (NOCATE); BzThi3-Octreotide (BOC); BzThi3,Thrs-Octreotide (BOCATE); JR11 ; BASS; and KE121.

[0032] 11 . The compound or salt in accordance with item 10, wherein the targeting moiety RTis a targeting moiety RTATEhaving the following structure (TA-1):

[0033] wherein the waved line marks a bond which attaches the moiety to the remainder of the compound.

[0034] 12. The compound or salt in accordance with item 9, wherein the targeting moiety RTis a targeting moiety RCPCR4which targets a C-X-C chemokine receptor type 4 (CXCR4) and has the following structure (TA-2): (TA-2) wherein

[0035] RB1is selected from hydrogen (-H) and iodine (-I), and is preferably H,

[0036] RB2is an alkanediyl group, preferably propanediyl, and most preferably -CH2-CH2-CH2-, and wherein the waved line marks a bond which attaches the moiety to the remainder of the compound.

[0037] 13. The compound or salt in accordance with item 9, wherein the targeting moiety RTis a targeting moiety RGRPRwhich targets a gastrin releasing peptide receptor (GRPR) and has the following structure (TA-3):

[0038] (TA-3) wherein the waved line marks a bond which attaches the moiety to the remainder of the compound, and wherein: RB3is selected from -CH2-CH2-C(O)-NH2 and -CH2-CH2-CH2OH, and is preferably -CH2-CH2- C(O)-NH2,

[0039] RB4is selected from -H and -CH3, and is preferably -CH3, and

[0040] XBis selected from NH and S, and is preferably NH.

[0041] 14. The compound or salt in accordance with item 9, wherein the targeting moiety RTis a targeting moiety RPSMAwhich targets a prostate specific membrane antigen and has the following structure (TA-4): (TA-4) wherein: m is an integer of 2 to 6, preferably 2 to 4, more preferably 2; n is an integer of 1 to 6, preferably 2 to 4, more preferably 2 or 4;

[0042] RB5is CH2, NH or O, preferably NH;

[0043] RB7is CH2, NH or O, preferably NH;

[0044] RB6is C or P(OH), preferably C;

[0045] XB2is NH or C(O); and wherein the waved line marks the bond which attaches the moiety to the remainder of the compound.

[0046] 15. The compound or salt in accordance with item 9, wherein the targeting moiety RTis a targeting moiety which targets GLP-1 R, and which is a peptide moiety provided by a peptide selected from GLP-1 and Exendin-4.

[0047] 16. The compound or salt in accordance with item 9, wherein the targeting moiety RTis a peptide moiety provided by a cyclic RGD peptide or a peptidomimetic of the type of Cilengitide, c(f(NMe)VRGD), cyclo(RGDfK(Ahx)) addressing different integrin isoforms.

[0048] 17. The compound or salt in accordance with item 9, wherein the targeting moiety RTis a targeting moiety which targets neurokinin-1 , and which is a peptide moiety provided by the peptide Substance P. 18. The compound or salt in accordance with item 9, wherein the targeting moiety RTis a targeting moiety which targets CCK2, and which is a peptide moiety selected from the group consisting of: -D-Glu-D-Glu-D-Glu-D-Glu-D-Glu-D-Glu-L-Ala-L-Tyr-Gly-L-Trp-L-Met-L-Asp-L-Phe-NH2, -D-Glu-D-Glu-D-Glu-D-Glu-D-Glu-D-Glu-L-Ala-L-Tyr-Gly-L-Trp-L-Nle-L-Asp-L-Phe-NH2, and -D-Glu-L-Ala-L-Tyr-Gly-L-Trp-L-(N-Me)Nle-L-Asp-L-1 Nal-NH2.

[0049] 19. The compound or salt in accordance with item 9, wherein the targeting moiety RTis a targeting moiety RFAPwhich is targets FAP and has one of the following structures (TA-5) or (TA-6): wherein

[0050] XB3is selected from O, NH and N(CH3),

[0051] RB8and RB9are identical or different, preferably identical, and are selected from H and F,

[0052] RB1° is selected from -CN and -COOH and is preferably -CN,

[0053] RB11and RB12are identical or different, preferably identical, and are selected from H and F, and are more preferably both F,

[0054] RB13is selected from -CN and -COOH and is preferably -COOH, and wherein the waved line marks the bond which attaches the moiety to the remainder of the compound. 20. The compound or salt in accordance with item 9, wherein the targeting moiety RTis a peptide moiety provided by the blood brain barrier (BBB)-crossing peptide PepH3 (AGILKRW and D-AGILKRW).

[0055] 21 . The compound or salt in accordance with any one of items 1 to 20, wherein each of L1Aand L1Bis selected from a divalent amino acid moiety and a divalent oligopeptide moiety, or is absent.

[0056] 22. The compound or salt in accordance with item 21 , wherein the divalent oligopeptide moiety comprises 2 to 5, preferably 2 or 3 amino acid units.

[0057] 23. The compound or salt in accordance with item 21 or 22, wherein the divalent amino acid moiety is a moiety derived from a hydrophilic amino acid which comprises, together with a carboxylic acid group and an amino group, one or more further hydrophilic functional groups selected from an ether bond -O-, -NH2, -COOH, -NH-C(=NH)-NH2, -C(=O)NH2,and -NH-C(=O)-NH2;and wherein the divalent oligopeptide moiety comprises at least one, preferably at least two, amino acid units independently derived from a hydrophilic amino acid which comprises, together with a carboxylic acid group and an amino group, one or more further hydrophilic functional groups selected from an ether bond -O-, -NH2, -COOH, -NH-C(=NH)-NH2, -C(=O)NH2, and -NH-C(=O)-NH2.

[0058] 24. The compound or salt in accordance with any one of items 1 to 23, wherein

[0059] L1Ais absent or contains a chain of 3 to 20, preferably 3 to 15, atoms extending from RTto the carbonyl group to which L1Ais attached; and

[0060] L1Bis absent or contains a chain of 3 to 20, preferably 3 to 15, atoms extending from RTto the nitrogen atom to which L1Bis attached.

[0061] 25. The compound or salt in accordance with any one of items 1 to 24, wherein each of L2Aand L2Bis selected from a divalent amino acid moiety and a divalent oligopeptide moiety, or is absent.

[0062] 26. The compound or salt in accordance with item 25, wherein the divalent oligopeptide moiety comprises 2 to 7, preferably 2 to 6 amino acid units.

[0063] 27. The compound or salt in accordance with item 25 or 26, wherein the divalent amino acid moiety is a moiety derived from a hydrophilic amino acid which comprises, together with a carboxylic acid group and an amino group, one or more further hydrophilic functional groups selected from -NH2, -COOH,-NH-C(=NH)-NH2, -C(=O)NH2,and -NH-C(=O)-NH2;and wherein the divalent oligopeptide moiety comprises at least two amino acid units independently derived from a hydrophilic amino acid which comprises, together with a carboxylic acid group and an amino group, one or more further hydrophilic functional groups selected from -NH2, -COOH, -NH-C(=NH)-NH2, -C(=O)NH2, and -NH-C(=O)-NH2.

[0064] 28. The compound or salt in accordance with any one of items 1 to 27, wherein

[0065] L2Ais absent or contains a chain of 3 to 25, preferably 3 to 20, atoms extending from RCHto the nitrogen atom to which L2Ais attached; and

[0066] L2Bis absent or contains a chain of 3 to 25, preferably 3 to 20, atoms extending from RCHto the carbonyl group to which L2Bis attached.

[0067] 29. The compound or salt in accordance with any of items 1 to 28, which is a radiolabeled compound or salt wherein RCHrepresents a chelate group comprising a complexed radioactive metal cation and the fluorine atom F attached to the silicon atom Si is [19F]fluorine.

[0068] 30. The compound or salt in accordance with any of items 1 to 28, which is a radiolabeled compound or salt wherein RCHrepresents a chelating group which is free of a complexed cation or a chelate group which comprises a complexed non-radioactive metal cation, and the fluorine atom F attached to the silicon atom Si is [18F]fluorine.

[0069] 31. A pharmaceutical composition comprising or consisting of one or more compounds or salts in accordance with any of items 1 to 30.

[0070] 32. The pharmaceutical composition in accordance with item 31 , which further comprises a pharmaceutically acceptable excipient.

[0071] 33. The compound or salt in accordance with any of items 1 to 30 for use as a medicament.

[0072] 34. The compound or salt in accordance with any of items 1 to 30 or the pharmaceutical composition of item 31 or 32 for use in a method for the treatment of a disease or disorder via radioligand therapy. 35. The compound or salt in accordance with any of items 1 to 30 or the pharmaceutical composition of item 31 or 32 for use in a method for the treatment of cancer.

[0073] 36. The compound or salt in accordance with any of items 1 to 30 or the pharmaceutical composition of item 31 or 32 for use in a method of diagnosis in vivo of a disease or disorder.

[0074] 37. The compound or salt or the pharmaceutical composition for use of item 36, wherein the disease or disorder is cancer.

[0075] 38. The compound or salt or the diagnostic composition for use of item 36 or 37, wherein the method of diagnosis involves nuclear diagnostic imaging.

[0076] As noted above, the present invention provides compounds of the formula (IA), compounds of formula (IB), and salts of these compounds.

[0077] The compounds of formula (IA) or (IB) have the following structure:

[0078] (IB) wherein RTrepresents a targeting moiety which targets a structure of therapeutic and / or diagnostic interest;

[0079] L1Aand L1Beach independently represents a divalent linking group, or is absent;

[0080] L2Aand L2Beach independently represents a divalent linking group, or is absent;

[0081] RCHrepresents (i) a chelating group or (ii) a chelate group wherein the chelating group comprises a complexed radioactive or non-radioactive metal cation, and the fluorine atom F attached to the silicon atom Si in formula (IA) and in formula (IB) is independently selected from radioactive [18F]fluorine and non-radioactive [19F]fluorine.

[0082] It should be understood that, unless indicated to the contrary, any reference to a compound of the invention herein encompasses the compounds of formula (IA) and (IB) (and the preferred embodiments of this formula disclosed herein), and the salts thereof. Thus, to the extent that groups contained in the compounds of the invention as discussed herein can form a salt, e.g. via protonation or via deprotonation, the indication of the structure of these groups encompasses the respective salts as well. Likewise, any racemates, enantiomers, or diastereomers of any chiral compounds of formula (IA) and (IB) and their salts are encompassed, unless a specific stereochemistry of the compound under consideration is indicated in a specific context. The compounds of the invention may also be referred to herein as ligand compounds of the invention, or briefly as ligands.

[0083] Due to the presence of the fluorine atom linked to the silicon atom in the above formulae, the compounds in accordance with the invention can be radiolabeled using radioactive [18F]fluorine in this position. Moreover, the compounds can be provided in the form of a radiolabeled compound containing a complexed radioactive metal cation. They are thus suitable for use as radiopharmaceuticals, both in diagnosis and in therapy. Since the compounds in accordance with the invention offer the possibility of achieving the radiolabeling with radioactive fluorine by covalent attachment of the fluorine to the compounds of the invention, or by chelating a radioactive metal cation, they are also referred to as radiohybrid compounds.

[0084] Among the compounds of formula (IA) and (IB), preference is given to the compounds of formula (IA).

[0085] A common characteristic of the compounds in accordance with the invention is the presence of a new type of silicon-based fluoride acceptor (SiFA) group having the following structure:

[0086] which is inserted as a bridging group between a targeting moiety RTand a chelating group / chelate group RCH. As will be understood by the skilled reader, one of the waved lines contained in the above formula marks the bond which is used to attach the silicon-based fluoride acceptor group to a linker L1Aor L1B, respectively, or, if this linker is absent, directly to a targeting moiety RT. The other one of the waved lines contained in the above formula marks the bond which is used to attach the silicon-based fluoride acceptor group to a linker L2Aor L2B, respectively, or, if this linker is absent, directly to a chelating group / chelate group RCH.

[0087] This divalent group, which is also referred to as the silicon-based fluoride acceptor group or SiFA group used in the present invention, or used in the compounds of the present invention, contains a fluorine atom and two tert-butyl groups covalently attached to a silicon atom which, in turn, is attached to a phenyl ring. Moreover, it provides a substituent -C(O)- in meta position to the Si containing substituent. For the sake of simplicity, the carbon atom of the concerned carbonyl function may also be referred to herein as the C-terminus of the SiFA group. At the other meta position relative to the Si containing substituent, a substituent -CH2-NH- is provided, the nitrogen atom of which may be referred to herein as the N-terminus of the SiFA group.

[0088] Reference made herein to an amino acid is directed, in line with the skilled person’s understanding, to a compound which comprises at least one amino group and at least one carboxylic acid group in the same molecule. One or more further functional groups may be contained in an amino acid. For example, an amino acid may comprise, together with an amino group and a carboxylic acid group, one or more further hydrophilic functional groups independently selected from a further amino group, a further carboxylic acid group, an ether bond -O-, a group -NH-C(=NH)-NH2, a group -C(=O)NH2,and a group -NH-C(=O)-NH2. Alternatively, amino acids can include non-polar side chains, hydrophobic, featuring aliphatic and aromatic groups. An amino acid may be a natural or a synthetic amino acid.

[0089] Accordingly, an amino acid moiety (or amino acid unit) which can be comprised by a compound in accordance with the invention is a moiety which is provided by an amino acid. A specific amino acid moiety can be identified by the name of the amino acid from which it can be derived, e.g. as a lysine moiety, glutamic acid moiety, etc.. An amino acid moiety may be a monovalent amino acid moiety, a divalent amino acid moiety, or a tri- or higher valent amino acid moiety. As will be understood by a skilled person, a monovalent amino acid moiety can be provided by converting one of the functional groups comprised by an amino acid into a coupling group which attaches the amino acid moiety to an adjacent moiety or group in the compound in accordance with the invention. Likewise, a divalent amino acid moiety can be provided by converting two of the functional groups comprised by an amino acid into coupling groups which attach the amino acid moiety to two adjacent moieties or groups in the compound in accordance with the invention. Typically, functional groups used for this purpose are an amino group which is converted to a coupling group -NH- or a carboxylic acid group which is converted to a coupling group -C(O)-. Preferably, a coupling group -NH- or -C(O)- comprised by such an amino acid moiety forms an amide or peptide bond -C(O)-NH- with an adjacent moiety or group. A tri- or higher valent amino acid moiety can be derived accordingly from an amino acid comprising one or more further functional groups in addition to the at least one amino group and at least one carboxylic acid group characterizing an amino acid.

[0090] In line with the common use of the term, a peptide moiety as referred to herein is a moiety containing two or more amino acid moieties which are attached to each other via an amide or peptide bond (-C(O)-NH-). Such amino acid moieties forming a peptide moiety may also be referred to as amino acid units of the peptide moiety. An amide or peptide bond formed between the amino acid moieties or units of the peptide moiety can be, but does not have to be, an a-peptide bond. Unless indicated otherwise in a specific context, an oligopeptide moiety is a peptide moiety which contains two to ten amino acid moieties or units. Peptide moieties containing more than 10 amino acid moieties or units may also be referred to as polypeptide moieties. Thus, the term peptide moiety covers both oligopeptide moieties and polypeptide moieties. Amino acid moieties or units forming a peptide moiety may form, e.g., an unbranched chain of amino acid moieties or units. As noted above, the bonds formed between the amino acid moieties or units in such a chain can be, but do not have to be, a-peptide bonds. Unless indicated otherwise, a peptide moiety as referred to herein may also be a peptide moiety comprising a cyclic peptide structure formed by amino acid units, e.g. by three or more, such as three to ten amino acid units. Such a peptide moiety comprising a cyclic peptide structure may additionally comprise amino acid units which are attached to the cyclic structure but which do not form a part of the cycle itself, e.g. as a branch structure attached to the cycle, so that a part of or all of the amino acid units in the peptide moiety comprising a cyclic peptide structure may be involved in the formed cyclic peptide structure. Chelating Group / Chelate Group RCH

[0091] The group RCHin the compounds of formula (IA) and (IB) represents a chelating group or a chelate group wherein the chelating group comprises a complexed radioactive or nonradioactive metal cation. In line with the skilled person’s understanding, the chelating group is typically a group which is suitable as a chelating ligand to form a chelate complex with a complexed radioactive or non-radioactive metal cation. The chelate group is a group wherein the chelating group has already formed a chelate complex with a radioactive or non-radioactive metal cation.

[0092] For example, a chelating group may comprise at least one of a macrocyclic ring structure with 8 to 20 ring atoms of which 2 or more, preferably 3 or more, are selected from oxygen atoms, sulfur atoms and nitrogen atoms; and an acyclic, open chain chelating structure with 8 to 20 main chain atoms of which 2 or more, preferably 3 or more are heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms.

[0093] Exemplary chelating groups RCHare chelating groups provided by a chelating agent selected from the group consisting of diethylenetriaminepentamethylenephosphonic acid (EDTMP), diethylenetriaminepentaacetic acid (DTPA), bis(carboxymethyl)-1 ,4,8,11-tetraaza- bicyclo[6.6.2] hexadecane (CBTE2a), cyclohexyl-1 ,2-diaminetetraacetic acid (CDTA), 4- (1 ,4,8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N'-[5- [acetyl(hydroxy)amino]-,pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]- amino]pentyl]-N-hydroxybutandiamide (DFO), 1 ,4,7, 10- tetraazacyclododecane- 1 ,7-diacetic acid (DO2A), 1 ,4,7,10-tetraazacyclododecan-N,N',N",N"'-tetraacetic acid (DOTA), 2-[1 ,4,7,10- tetraazacyclododecane-4,7,10-triacetic acid]-pentanedioic acid (DOTAGA or DOTA-GA),

[0094] 1.4.7.10-tetrakis(carbamoylmethyl)-1 ,4,7,10-tetraazacyclododecane (DOTAM), N,N'- dipyridoxylethylendiamine-N,N'-diacetate-5,5'-bis(phosphate) (DPDP), ethylenediamine-N,N'- tetraacetic acid (EDTA), ethyleneglykol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1 ,4,7,10-tetraazacyclodecan-

[0095] 4.7.10-triacetate (HP-DOA3), 1 , 4, 7-triazacyclononan-1 -succinic acid-4, 7-diacetic acid

[0096] (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1 ,4,7-triazacyclononane

[0097] (NODAGA), 1 ,4,7-triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1 ,4,8,11- tetraazabicyclo[6.6.2]hexadecane (TE2A), 1 ,4, 8,11-tetraazacyclododecane-1 ,4,8,11- tetra-'acetic acid (TETA), terpyridine-bis(methyleneamine) tetraacetic acid (TMT), 1 ,4,7,10- tetraazacyclotridecan-N,N',N",N"'-tetraacetic acid (TRITA), triethylenetetraaminehexaacetic acid (TTHA), N,N'-bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (Fhmacropa), 4- amino-4-{2-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1 ,4-dihydro-pyridin-2-ylmethyl)-carbamoyl]-ethyl} heptanedioic acid bis-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1 ,4-dihydro-pyridin-2-ylmethyl)-amide]

[0098] (THP), 1 ,4,7-triazacyclononane-1 ,4,7-tris[methylene(2-carboxyethyl)phosphinic acid (TRAP), 2-(4 , 7, 10-tris(2-amino-2-oxoethyl)-1 ,4,7, 10-tetraazacyclododecan-1-yl)acetic acid (DO3AM),

[0099] 1 ,4,7,10-tetraazacyclododecane-1 ,4,7, 10-tetrakis[methylene(2-carboxyethylphosphinic acid)] (DOTPI), S-2-(4-isothiocyanatobenzyl)-1 ,4,7,10-tetraazacyclododecane tetraacetic acid, hydrazinonicotinic acid (HYNIC), 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]- eicosan-1 ,8-diamine (SarAr), 6-Amino-6-methylperhydro-1 ,4-diazepine-N,N,N',N'-tetraacetic acid (AAZTA), (6-pentanoic acid)-6-(amino)methyl-1 ,4-diazepine triacetate (DATA), pentadeca-1 ,4,7,10,13-penta-aminopentaacetic acid (PEPA), hexadeca-1 , 4,7,10,13,16- hexaamine-hexaacetic acid (HEHR), 4-{[bis(phosphonomethyl)) carbamoyl]methyl}-7,10-bis

[0100] (carboxymethyl)-1 ,4,7,10-tetraazacyclododec-1-yl) acetic acid (BPAMD), N (4-{[bis

[0101] (phosphonomethyl)) carbamoyl] methyl}-7,10-bis(carboxymethyl)-nona-1 ,4,7-triamine triacetic acid (BPAM), 1 ,2-[{6-(carboxylate) pyridin-2-yl} methylamine] ethane (DEDPA, H2DEDPA), deferoxamine (DFO), deferiprone, (4-acetylamino-4-yl) {2-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1,4- dihydro-pyridin-2-ylmethyl) -carbamoyl]-ethyl}-heptanedioic acid bis-[(3-hydroxy-1 ,6-dimethyl-

[0102] 4-oxo-1 ,4-dihydro-pyridin-2-ylmethyl)-amide] (CP256), YM103, tetraazycyclodecane- phosphinic acid (TEAP), 6,6'-[{9-hydroxy-1 ,5-bis-(methoxycarbonyl)-2,4-di(pyridin-2-yl)-3,7- diazabicyclo[3.3.1]nonane-3,7-diyl}bis(methylene)]dipicolinic acid (H2bispa2), 1 ,2-[{6- (carboxylato)pyridin-2-yl}methylamino]-ethane (H2dedpa), N,N'-bis(6-carboxy-2- pyridylmethyl)-ethylenediamine-N,N'-diacetic acid (H4octapa), N,N'-bis(2-hydroxy-5- sulfonylbenzyl)-N,N'-bis-(2-methylpyridyl)ethylenediamine (HeSbbpen), triethylenetetramine-

[0103] N,N,N',N",N"',N"'-hexaacetic (TTHA), 2-aminomethylpiperidine triacetic acid (2-AMPTA), 2-(N- (2-Hydroxybenzyl)aminomethyl)piperidine (2-AMPTA-HB), 4-nitro-2-hydroxybenzyl-2-{[(6)- trans-2-[benzyl(carboxymethyl)amino] cyclohexyl] (carboxymethyl)amino}acetic acid (RESCA), and 6-carboxy-1 , 4, 8, 11 -tetraazaundecane (N4).

[0104] Exemplary chelate groups RCHare chelate groups wherein any one of the exemplary chelating groups comprises a complexed radioactive or non-radioactive metal cation.

[0105] Preferably, RCHrepresents a chelating group which is provided by a chelating agent selected from the group consisting of DOTA, DOTAGA, DOTAM, DO3AM, NOTA and NODAGA, more preferably from DOTA and DOTAGA, or a chelate group wherein any one of these chelating groups comprises a complexed radioactive or non-radioactive metal cation.

[0106] As will be understood by the skilled reader, the above exemplary and preferred chelating groups can be provided by converting a functional group, such as an amino group, a carboxylic acid group or an amide group, comprised by the corresponding chelating agent, into a coupling group which serves to attach the chelating group (or the chelate group comprising it) to the remainder of the compound in accordance with the invention. Preferably, the chelating group comprises a coupling group -NH- or -C(O)- which forms an amide or peptide bond -C(O)-NH- with L2Aor L2B, respectively, or if the linking group is absent, with the N- or the C-terminus of the silicon-based fluoride acceptor group used in the compounds in accordance with the invention. It is particularly preferred if the chelating group comprises a coupling group -C(O)- which forms an amide or peptide bond -C(O)-NH- with L2Aor L2B, respectively, or if the linking group L2Ain the compound of formula (IA) is absent, with the N-terminus of the silicon-based fluoride acceptor group used in the compounds of formula (IA).

[0107] As exemplary metal cations which may be complexed in a chelate group RCH, reference can be made to a metal cation selected from cations of43Sc,44Sc,47Sc,51Cr,52mMn,55Co,57Co,58Co,52Fe,56Ni,57Ni,62Cu,64Cu,67Cu,66Ga,68Ga,67Ga,89Zr,90Y,86Y,94mTc,99mTc,97Ru,105Rh,109Pd,111Ag,110mln,111ln,113mln,114mln,117mSn,121Sn,127Te,142Pr,143Pr,147Nd,149Gd,149Pm,151Pm,149Tb,152Tb,155Tb,153Sm,156Eu,157Gd,155Tb,161Tb,164Tb,161Ho,166Ho,157Dy,165Dy,166Dy,160Er,165Er,169Er,171Er,166Yb,169Yb,175Yb,167Tm,172Tm,177Lu,186Re,186gRe,188Re,188W,191Pt,195mPt,194lr,197Hg,198Au,199Au,212Pb,203Pb,211At,212Bi,213Bi,223Ra,224Ra,225Ac,226Th and227Th, and from cations of nonradioactive isotopes of any of these metals. The chelated cation may be a complex cation, e.g. a metal ion carrying an additional coordinated ligand other than the chelating moiety, such as an oxo-ligand in a chelate including a99mTc(V)-oxo core.

[0108] Preferably, the complexed metal cation in a chelate group RCHis selected fromnatGa3+,68Ga3+,natLu3+,177Lu3+,90Y3+andnatY3+, more preferably fromnatGa3+,68Ga3+,natLu3+, and177Lu3+.

[0109] In line with the above, it is particularly preferred if RCHrepresents a chelating group of formula (CH-1) (also referred to herein as the DOTA chelating group) or a chelate group of any of formulae (CH-2) or (CH-3): wherein the waved line marks a bond which attaches the group to the remainder of the compound, the complexed Lu3+cation in formula (CH-2) is selected from a cation of non-radioactivenatLu and a cation of radioactive177Lu, and the complexed Ga3+cation is selected from a cation of non-radioactivenatGa and a cation of radioactive68Ga.

[0110] As will be understood by the skilled reader, electron lone pairs provided by the nitrogen atoms and by the carboxylate in formulae (CH-2) and (CH-3) form coordinative bonds (not shown in the formulae) with the complexed metal cations.

[0111] Preferably, the carbonyl group -C(O) from which the bond marked with the waved line extends in formulae (CH-1), (CH-2) and (CH-3) forms an amide or peptide bond -C(O)-NH- with L2Aor L2B, respectively, or, if the linking group L2Ain the compound of formula (IA) is absent, with the N-terminus of the silicon-based fluoride acceptor group used in the compounds of formula (IA).

[0112] Since, as noted above, salts of the compounds of formula (IA) and (IB) are also compounds in accordance with the invention, it will be understood that the above groups may also be involved in the formation of a salt, e.g. via the deprotonation of one or more of the carboxylic acid groups of the chelating group (CH-1), and such a salt is also encompassed by the invention.

[0113] In line with the above, preferred compounds in accordance with the invention are: a compound of formula (IA), wherein RCHis selected from a group of formula (CH-1), (CH-2) and (CH-3), or a salt thereof, and a compound of formula (IB), wherein RCHis selected from a group of formula (CH-1), (CH-2) and (CH-3), or a salt thereof.

[0114] Targeting Moiety RT

[0115] The group RTin the compounds of formula (IA) or (IB) or the preferred forms thereof represents a targeting moiety which targets a structure of therapeutic and / or diagnostic interest. The skilled person will be aware that a wide variety of such targeting moieties are described in the literature, e.g. related to radiodiagnosis or radioligand therapy, which can be used in the context of the present invention.

[0116] The targeting moiety RTtargets a structure of therapeutic and / or diagnostic interest, i.e. the structure may be of therapeutic interest, of diagnostic interest, or both. This structure, to which the targeting moiety is directed, may also be referred to herein as the target structure for a compound in accordance with the invention. Preferably, the target structure is a structure of therapeutic and diagnostic interest in view of the radiohybrid characteristics of the compounds in accordance with the invention discussed herein.

[0117] As will be understood by the skilled reader, the structure of therapeutic and / or diagnostic interest is generally a physiological structure which can be present in the body of a patient, e.g. a human patient. For example, the structure of therapeutic and / or diagnostic interest may be a structure which is present in the body of a patient suffering from a disease or disorder, but not in the body of a healthy patient, or a structure which is present in the body of a patient suffering from a disease or disorder in an amount differing from the amount present in the body of a healthy patient.

[0118] As will be further understood, a targeting moiety which targets a structure of therapeutic and / or diagnostic interest (which may also be referred to as a targeting moiety which is directed to a structure of therapeutic and / or diagnostic interest herein), generally has an affinity for the target structure. This affinity allows compounds comprising the targeting moiety to accumulate at the site of the target structure. Preferably, the targeting moiety is able to selectively bind to the target structure. For example, a compound in accordance with the invention comprising the targeting moiety RTmay bind with a target structure with high affinity, e.g. as indicated by an IC50 in the low nanomolar range, preferably 50 nM or less, more preferably 20 nM or less, still more preferably 10 nM or less. The half maximal inhibitory concentration (IC50) is the quantitative measure of the molar concentration of a compound according to the invention comprising the targeting moiety RTwhich is necessary to inhibit the binding of a radioactive reference ligand to the target structure in vitro by 50%. As will be understood, a selective binding to the target structure generally means that the target structure is preferred as a binding partner for the targeting moiety (e.g. in terms of the bond strength or the stability of the bond achieved) compared to other structures which may be contacted by the targeting moiety during diagnosis and / or therapy.

[0119] For example, the targeting moiety RTmay represent a targeting moiety which targets a structure, preferably a targeting structure which is able to selectively bind to a structure, selected from the group consisting of a somatostatin receptor (SSTR), a gastrin releasing peptide receptor (GRPR), a C-X-C chemokine receptor type 4 (CXCR4), a glucagon-like peptide-1 receptor (GLP1 R), a cholecystokinin B receptor (CCKBR or CCK2), prostate specific membrane antigen (PSMA), fibroblast activation protein alpha (FAP), an integrin binding ligand, and neurokinin-1 , or is a blood brain barrier crossing peptide. More preferably, the targeting moiety RTrepresents a targeting moiety which is able to selectively bind to a structure selected from the group consisting of a somatostatin receptor (SSTR), a gastrin releasing peptide receptor (GRPR), and a C-X-C chemokine receptor type 4 (CXCR4).

[0120] In terms of the structure of the targeting moiety, it is preferred that the targeting moiety RTrepresents a peptide moiety. Alternatively, it may, e.g., be a moiety which is provided by a small molecule. It is more preferred that RTis a peptide moiety which comprises 3 to 20 amino acid units, and still more preferably a peptide moiety which comprises 3 to 10 amino acid units. For example, the peptide moiety as RTmay represent a linear chain of amino acid units or may represent a peptide moiety comprising a cyclic peptide structure. Preferably, the peptide moiety provides a coupling group -NH- as an N-terminus or a coupling group -C(O)- as a C terminus which forms an amide or peptide bond -C(O)-NH- with L1Aor L1B, respectively, or if the linking group is absent, with the N- or the C-terminus of the silicon-based fluoride acceptor group used in the compounds in accordance with the invention. As examples for a targeting moiety RTwhich targets a somatostatin receptor, reference can be made to a targeting moiety which can be derived from a receptor agonist or receptor antagonist selected from the group consisting of Tyr^Thr^-Octreotide (TATE); Tyr3-Octreotide (TOC); Thi^-Octreotide (ATE); 1-Nal3-Octreotide (NOC); 1-Nal3,Thr®-Octreotide (NOCATE); BzThi3-Octreotide (BOC); BzThi3,Thrs-Octreotide (BOCATE); JR11 (H-L-Cpa-cyc / o(D-Cys-L- Aph(Hor)-D-Aph(Cbm)-L-Lys-L-Thr-L-Cys)-D-Tyr-NH2); BASS (H-L-Phe(4-NO2)-cyc / o(D-Cys- L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-D-Tyr-NH2); and KE121 (cyc / o(D-Dab-L-Arg-L-Phe-L-Phe-D- Trp-L-Lys-L-Thr-L-Phe). As will be understood by the skilled reader, a targeting moiety RTcan be conveniently derived from the receptor agonists or antagonists listed above by using a functional group, such as a carboxylic acid group or an amino group, contained in the receptor agonist or antagonist, to provide a coupling group which attaches the group RTto the remainder of the compound, preferably as a part of an amide or peptide bond -C(O)-NH-.

[0121] A preferred example for a targeting moiety RTwhich targets a somatostatin receptor is the targeting moiety RTATEhaving the following structure (TA-1): wherein the waved line marks a bond which attaches the moiety to the remainder of the compound. Preferably, the moiety provides the stereochemistry shown in formula (TA-1.1):

[0122]

[0123] Preferably, the group -NH from which the bond marked with the waved line extends in formulae (TA-1) or (TA-1.1) forms an amide or peptide bond -C(O)-NH- with L1Aor L1B, respectively, or, if the linking group L1Ain the compound of formula (IA) is absent, with the C-terminus of the silicon-based fluoride acceptor group used in the compounds of formula (IA).

[0124] Since, as noted above, salts of the compounds of formula (IA) and (IB) are also compounds in accordance with the invention, it will be understood that the above groups (TA-1) or (TA-1.1) may also be involved in the formation of a salt, e.g. via the protonation of an amino group, and such a salt is also encompassed by the invention.

[0125] A preferred example for a targeting moiety RTwhich targets a C-X-C chemokine receptor type- 4 is the targeting moiety RCPCR4having the following structure (TA-2):

[0126] wherein

[0127] RB1is selected from hydrogen (-H) and iodine (-I), and is preferably H, RB2is an alkanediyl group, preferably propanediyl, and most preferably -CH2-CH2-CH2-, and wherein the waved line marks a bond which attaches the moiety to the remainder of the compound.

[0128] Preferably, the moiety of formula (TA-2) includes RB2as -CH2-CH2-CH2- and provides the stereochemistry shown in formula (TA-2.1): (TA-2.1) wherein RB1is selected from hydrogen (-H) and iodine (-I), and is preferably H, and wherein the waved line marks a bond which attaches the moiety to the remainder of the compound.

[0129] Preferably, the group -NH from which the bond marked with the waved line extends in formulae (TA-2) or (TA-2.1) forms an amide or peptide bond -C(O)-NH- with L1Aor L1B, respectively, or, if the linking group L1Ain the compound of formula (IA) is absent, with the C-terminus of the silicon-based fluoride acceptor group used in the compounds of formula (IA).

[0130] Since, as noted above, salts of the compounds of formula (IA) and (IB) are also compounds in accordance with the invention, it will be understood that the above groups (TA-2) or (TA-2.1) may also be involved in the formation of a salt, e.g. via the protonation of a suitable nitrogen atom, and such a salt is also encompassed by the invention.

[0131] A preferred example for a targeting moiety RTwhich targets a gastrin releasing peptide receptor (GRPR) receptor is the targeting moiety RGPRPhaving the following structure (TA-3):

[0132]

[0133] (TA-3) wherein the waved line marks a bond which attaches the moiety to the remainder of the compound, and wherein:

[0134] RB3is selected from -CH2-CH2-C(O)-NH2 and -CH2-CH2-CH2OH, and is preferably -CH2-CH2- C(O)-NH2, RB4is selected from -H and -CH3, and is preferably -CH3, and XBis selected from NH and S, and is preferably NH.

[0135] Preferably, the moiety of formula (TA-3) provides the stereochemistry shown in formula (TA- 3.1), wherein, as will be understood, the variables maintain their meanings and preferred meanings as indicated for formula (TA-3):

[0136]

[0137] (TA-3.1) Preferably, the group -NH from which the bond marked with the waved line extends in formulae (TA-3) or (TA-3.1) forms an amide or peptide bond -C(O)-NH- with L1Aor L1B, respectively, or, if the linking group L1Ain the compound of formula (IA) is absent, with the C-terminus of the silicon-based fluoride acceptor group used in the compounds of formula (IA). Since, as noted above, salts of the compounds of formula (IA) and (IB) are also compounds in accordance with the invention, it will be understood that the above groups (TA-3) or (TA-3.1) may also be involved in the formation of a salt, e.g. via the protonation of a suitable nitrogen atom, and such a salt is also encompassed by the invention. A preferred example for a targeting moiety RTwhich targets a prostate specific membrane antigen is the targeting moiety RPSMAhaving the following structure (TA-4): (TA-4) wherein: m is an integer of 2 to 6, preferably 2 to 4, more preferably 2; n is an integer of 1 to 6, preferably 2 to 4, more preferably 2 or 4;

[0138] RB5is CH2, NH or O, preferably NH;

[0139] RB7is CH2, NH or O, preferably NH;

[0140] RB6is C or P(OH), preferably C;

[0141] XB2is NH or C(O); and wherein the waved line marks the bond which attaches the moiety to the remainder of the compound.

[0142] As apparent from the above, a preferred form of this targeting moiety is a targeting moiety having the following structure (TA-4.1) wherein m, n and XB2are as defined above and the waved line marks a bond which attaches the moiety to the remainder of the compound. Preferably, the moiety provides the stereochemistry shown in formula (TA-4.2): wherein m, n and XB2are as defined above and the waved line marks a bond which attaches the moiety to the remainder of the compound.

[0143] For example, the group XB2can be a group -NH from which the bond marked with the waved line extends in formulae (TA-4), (TA-4.1), or (TA-4.2) and which forms an amide or peptide bond -C(O)-NH- with L1Aor L1B, respectively, or, if the linking group L1Ain the compound of formula (IA) is absent, with the C-terminus of the silicon-based fluoride acceptor group used in the compounds of formula (IA).

[0144] Since, as noted above, salts of the compounds of formula (IA) and (IB) are also compounds in accordance with the invention, it will be understood that the above groups (TA-4), (TA-4.1), or (TA-4.2) may also be involved in the formation of a salt, e.g. formed by one or more carboxylic acid groups, and such a salt is also encompassed by the invention.

[0145] As an example for a targeting moiety RTwhich targets GLP-1 R, reference can be made to a peptide moiety provided by a peptide selected from GLP-1 and Exendin-4.

[0146] As an example of a targeting moiety RTwhich targets an integrin, reference can be made to a a peptide moiety provided by a cyclic RGD peptide of the type of Cilengitide which selected from the group consisting of a5|31 , av|33, av|35, av|36.

[0147] As an example of targeting moiety RTwhich targets neurokinin-1 , reference can be made to a peptide moiety provided by the peptide Substance P.

[0148] As an example of a targeting moiety RTwhich targets CCK2, reference can be made to a peptide moiety selected from the group consisting of:

[0149] -D-Glu-D-Glu-D-Glu-D-Glu-D-Glu-D-Glu-L-Ala-L-Tyr-Gly-L-Trp-L-Met-L-Asp-L-Phe-NH2, -D-Glu-D-Glu-D-Glu-D-Glu-D-Glu-D-Glu-L-Ala-L-Tyr-Gly-L-Trp-L-Nle-L-Asp-L-Phe-NH2, and -D-Glu-L-Ala-L-Tyr-Gly-L-Trp-L-(N-Me)Nle-L-Asp-L-1 Nal-NH2.

[0150] As examples of a targeting moiety RTwhich target FAP and which are provided by small molecules, the following structures (TA-5) or (TA-6) may be mentioned:

[0151] wherein

[0152] XB3is selected from O, NH and N(CH3),

[0153] RB8and RB9are identical or different, preferably identical, and are selected from H and F,

[0154] RB1° is selected from -CN and -COOH and is preferably -CN,

[0155] RB11and RB12are identical or different, preferably identical, and are selected from H and F, and are more preferably both F,

[0156] RB13is selected from -CN and -COOH and is preferably -COOH, and wherein the waved line marks the bond which attaches the moiety to the remainder of the compound.

[0157] Since, as noted above, salts of the compounds of formula (IA) and (IB) are also compounds in accordance with the invention, it will be understood that the above groups (TA-5) or (TA-6) may also be involved in the formation of a salt, e.g. formed by a carboxylic acid group or by the protonation of a suitable nitrogen atom, and such a salt is also encompassed by the invention.

[0158] As an example of a targeting moiety RTwhich represents a blood-brain barrier crossing peptide reference can be made to a peptide moiety provided by the blood brain barrier (BBB)-crossing peptide PepH3 (AGILKRW and D-AGILKRW).

[0159] In line with the above, further preferred compounds in accordance with the invention are: a compound of formula (IA), wherein RCHis selected from a group of formula (CH-1), (CH-2) and (CH-3), and wherein RTis selected from a group of formula (TA-1), (TA-2) and (TA-3), or a salt thereof, and a compound of formula (IB), wherein RCHis selected from a group of formula (CH-1), (CH-2) and (CH-3), and wherein RTis selected from a group of formula (TA-1), (TA-2), and (TA-3), or a salt thereof, being understood that also in this context, compounds in accordance with the invention comprising further preferred forms of (TA-1), (TA-2), and (TA-3) as discussed above are further preferred.

[0160] Linker Structures

[0161] If L1Ain formula (IA) is not absent, it preferably comprises a terminal coupling group -NH- which forms an amide or peptide bond -C(O)-NH- with the C-terminal of the silicon-based fluoride acceptor group used in the invention to which L1Ais attached. If L1Ais absent, it will be understood that RTin formula (IA) is directly attached to the C-terminus of the silicon-based fluoride acceptor group used in the invention, preferably via an amide or peptide bond -C(O)-NH- formed by the C-terminal carbonyl group of the silicon-based fluoride acceptor group and a terminal coupling group -NH- provided by RT.

[0162] L1Bin formula (IB) is preferably not absent, and preferably comprises a terminal coupling group -C(O)- which forms an amide or peptide bond -C(O)-NH- with the N-terminal group of the silicon-based fluoride acceptor group use in the invention to which L1Bis attached. If L1Bis absent, it will be understood that RTin formula (IB) is directly attached to the N-terminus of the silicon-based fluoride acceptor group used in the invention, preferably via an amide or peptide bond -C(O)-NH- formed by the N-terminal group of the silicon-based fluoride acceptor group and a terminal coupling group -C(O)- provided by RT.

[0163] Preferably, L1Ais absent or is selected from a divalent amino acid moiety and a divalent oligopeptide moiety, e.g. in the form of an unbranched chain of amino acid units. A divalent oligopeptide moiety in this context preferably comprises 2 to 5, more preferably 2 or 3 amino acid units.

[0164] Preferably, L1Bis selected from a divalent amino acid moiety and a divalent oligopeptide moiety, e.g. in the form of an unbranched chain of amino acid units. A divalent oligopeptide moiety in this context preferably comprises 2 to 5, more preferably 2 or 3 amino acid units. As an example, the divalent amino acid moiety which may be represented by L1Aand L1Bmay be a moiety derived from a hydrophilic amino acid which comprises, together with a carboxylic acid group and an amino group, one or more further hydrophilic functional groups selected from an ether bond -O-, -NH2, -COOH, -NH-C(=NH)-NH2, -C(=O)NH2,and -NH-C(=O)-NH2.

[0165] As an example, the divalent oligopeptide acid moiety which may be represented by L1Aand L1Bmay comprise at least one, preferably at least two, amino acid units independently derived from a hydrophilic amino acid which comprises, together with a carboxylic acid group and an amino group, one or more further hydrophilic functional groups selected from an ether bond - O-, -NH2, -COOH, -NH-C(=NH)-NH2, -C(=O)NH2, and -NH-C(=O)-NH2.AIso in this context, the divalent oligopeptide moiety preferably comprises 2 to 5, more preferably 2 or 3 amino acid units.

[0166] Moreover, it is preferred that L1Ais absent or contains a chain of 3 to 20, preferably 3 to 15, atoms extending from RTto the carbonyl group to which L1Ais attached; and that L1Bcontains a chain of 3 to 20, preferably 3 to 15, atoms extending from RTto the nitrogen atom to which L1Bis attached.

[0167] If L2Ain formula (IA) is not absent, it preferably comprises a terminal coupling group -C(O)- which forms an amide or peptide bond -C(O)-NH- with the N-terminal group of the silicon- based fluoride acceptor group used in the invention to which L2Ais attached. If L2Ais absent, it will be understood that RCHin formula (IA) is directly attached to the N-terminus of the silicon- based fluoride acceptor group used in the invention, preferably via an amide or peptide bond -C(O)-NH- formed by the N-terminal group of the silicon-based fluoride acceptor group and a terminal coupling group -C(O)- provided by RCH.

[0168] L2Bin formula (IB) is preferably not absent and preferably comprises a terminal coupling group -NH- which forms an amide or peptide bond -C(O)-NH- with the C-terminal carbonyl group of the silicon-based fluoride acceptor group of the invention to which L2Bis attached. If L2Bis absent, it will be understood that RCHin formula (IB) is directly attached to the C-terminus of the silicon-based fluoride acceptor group used in the invention, preferably via an amide or peptide bond -C(O)-NH- formed by the C-terminal carbonyl group of the silicon-based fluoride acceptor group and a terminal coupling group -NH- provided by RCH.

[0169] Preferably, L2Ais absent or is selected from a divalent amino acid moiety and a divalent oligopeptide moiety, e.g. in the form of an unbranched chain of amino acid units. A divalent oligopeptide moiety in this context preferably comprises 2 to 7, more preferably 2 to 6 amino acid units.

[0170] Preferably, L2Bis selected from a divalent amino acid moiety and a divalent oligopeptide moiety, e.g. in the form of an unbranched chain of amino acid units. A divalent oligopeptide moiety in this context preferably comprises 2 to 7, more preferably 2 to 6 amino acid units.

[0171] As an example, the divalent amino acid moiety which may be represented by L2Aand L2Bmay be a moiety derived from a hydrophilic amino acid which comprises, together with a carboxylic acid group and an amino group, one or more further hydrophilic functional groups selected from -NH2, -COOH, -NH-C(=NH)-NH2, -C(=O)NH2,and -NH-C(=O)-NH2.

[0172] As an example, the divalent oligopeptide acid moiety which may be represented by L2Aand L2Bmay comprise at least two amino acid units independently derived from a hydrophilic amino acid which comprises, together with a carboxylic acid group and an amino group, one or more further hydrophilic functional groups selected from

[0173] -NH2, -COOH, -NH-C(=NH)-NH2, -C(=O)NH2, and -NH-C(=O)-NH2.

[0174] Moreover, it is preferred that L2Ais absent or contains a chain of 3 to 25, preferably 3 to 20, atoms extending from RCHto the nitrogen atom to which L2Ais attached; and L2Bcontains a chain of 3 to 25, preferably 3 to 20, atoms extending from RCHto the carbonyl group to which L2Bis attached.

[0175] As preferred compounds in accordance with the invention, reference is made to the compounds of the following formulae or to salts thereof:

[0176]

[0177] The first of the compounds above is also referred to as (SiFA)SeFe-rhTATE4 in the context of the present application. The second one is referred to as (SiFA)SeFe-rhCPCR4.1 and the third one as (SiFA)SeFe-rhGRPRI .

[0178] It will be understood that these preferred compounds or salts may also carry a non-radioactive [19F]-fluorine attached to the Si-atom shown in the formulae, or a radioactive [18F]-fluorine, and that both forms are encompassed by the invention.

[0179] Moreover, similar preference is given to chelate compounds or salts thereof wherein the DOTA chelating groups in the above formulae form a chelate complex with a radioactive or nonradioactive metal cation. As noted above, examples of suitable radioactive metal cations are68Ga3+,177Lu3+and90Y3+, whereas examples of suitable non-radioactive metal cations arenatGa3+,natLu3+andnatY3+. Thus, for example, a preferred compound of the invention is a chelate compound or a salt thereof wherein the fluoride attached to the Si-atom shown in the above formulae is a radioactive [18F]-fluorine, and the DOTA chelating group in the above formulae forms a chelate complex with a non-radioactive metal cation selected fromnatGa3+,nat|_u3+andnaty3+ Likewise, a preferred compound of the invention is a chelate compound or a salt thereof wherein the fluorine attached to the Si-atom shown in the above formulae is a non-radioactive [19F]-fluorine, and the DOTA chelating group in the above formulae forms a chelate complex with a radioactive metal cation selected from68Ga3+,177Lu3+and90y3+.

[0180] Salt Forms

[0181] As noted above, the compounds in accordance with the invention encompass compounds of formula (IA) or of formula (IB), as well as salts of the compounds of formula (IA) or of formula (IB), or of any preferred versions thereof. Such salts are preferably pharmaceutically acceptable salts, i.e. formed with pharmaceutically acceptable anions or cations. Salts may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as a nitrogen atom, with an inorganic or organic acid, or by separating a proton from an acidic group, such as a carboxy group, e.g. by neutralization with a base. It will be understood that the reference to compounds of formula (IA) or of formula (IB) and salts thereof will also encompass salts which involve charged forms of groups or moieties which may be contained in the compounds of formula (IA) or formula (IB), and which are further defined herein by their structure herein, such as charged forms of the chelating group (CH-1), or charged forms of the targeting moieties (TA-1), (TA-2), etc. Charged groups which may be present in the compounds in accordance with the invention and which may provide the compounds in the form of a salt include groups which are continuously charged, such as a quaternary ammonium group comprising an ammonium cation wherein the nitrogen is substituted by four organyl groups, or charged chelate complexes.

[0182] As exemplary anions which may be present as counterions in salt forms of the compounds of the invention if the salt form comprises a positively charged form of the compound, mention may be made, for example, of an anion selected from chloride, bromide, iodide, sulfate, nitrate, phosphate (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate, hydrogencarbonate or perchlorate; acetate, trifluoroacetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, undecanoate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, nicotinate, benzoate, salicylate or ascorbate; sulfonates such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate (tosylate), 2-naphthalenesulfonate, 3-phenylsulfonate, or camphorsulfonate. Since trifluoroacetic acid is frequently used during the synthesis of peptides, trifluoroacetate salts are typical salts which are provided if a compound comprising a peptide structure is formed. Such trifluoroacetate salts may be converted e.g. to acetate salts during their workup. Thus, trifluoroacetate salts or acetate salts are frequently encountered as salt forms.

[0183] As exemplary cations which may be present as counterions in salt forms of the compounds of the invention if the salt form comprises a negatively charged form of the compound, mention may be made, for example, of a cation selected from alkali metal cations, such as lithium, sodium or potassium, alkaline earth metal cations, such as calcium or magnesium; and ammonium (including ammonium ions substituted by organic groups). Radiolabeling and Pharmaceutical Aspects

[0184] The compounds in accordance with the invention comprise a silicon-based fluoride acceptor group wherein a fluorine atom F is attached via a direct covalent bond to a Si atom as shown in formulae (IA) and (IB). The F may be18F (i.e. a radioactive fluorine isotope) or19F (a nonradioactive fluorine isotope also referred to as “cold fluorine”). The silicon-based fluoride acceptor group used in the compounds in accordance with the invention allows a fast and efficient isotopic exchange reaction between19F and18F to be accomplished. Thus, the invention further provides a method for the preparation of a radiolabeled compound, comprising a step of reacting a compound in accordance with the invention wherein the fluorine attached via a direct covalent bond to the Si atom is [19F]fluorine, with [18F]fluoride to exchange the [19F]fluorine by [18F]fluorine. Sources of [18F]fluoride and setups which are known in the art for the isotopic exchange of19F to18F in conventional silicon-based fluoride acceptor groups can be relied on also in the context of the present invention . Reference can be made, e.g., to C. Wangler et al., Appl. Sci. 2012, 2(2), 277-302 or A. Wurzer et al., EJNMMI Radiopharm. Chem. 6, 4 (2021).

[0185] In line with the above, the compounds in accordance with the invention encompass radiolabeled compounds and non-radiolabeled compounds. Radiolabeled compounds of the invention are compounds containing a radioactive constituent i.e. in particular a [18F]fluorine atom or a radioactive metal cation complexed in a chelate group. As specific radiolabeled compounds in accordance with the invention, reference can be made to a radiolabeled compound or salt wherein RCHrepresents a chelate group comprising a complexed radioactive metal cation and the fluorine atom F attached to the silicon atom Si is [19F]fluorine, and to a radiolabeled compound or salt wherein RCHrepresents a chelating group which is free of a complexed cation or a chelate group which comprises a complexed non-radioactive metal cation, and the fluorine atom F attached to the silicon atom Si is [18F]fluorine. Non-radiolabeled compounds in accordance with the invention are compounds not containing a radioactive constituent, in particular compounds neither containing [18F]fluorine nor a complexed radioactive metal cation. Non-radiolabeled compounds in accordance with the invention may also be considered as precursors of radiopharmaceutical compounds, and in particular of the radiolabeled compounds in accordance with the invention as radiopharmaceuticals.

[0186] In another aspect, the invention provides a pharmaceutical composition, such as a radiopharmaceutical composition, comprising a compound in accordance with the invention, optionally in combination with a pharmaceutically acceptable excipient. A radiopharmaceutical composition is a pharmaceutical composition comprising a radiolabeled compound in accordance with the invention. Examples of pharmaceutically acceptable excipients are well known in the art and include phosphate buffered saline solutions, amino acid buffered solutions (with or without saline), water for injection, emulsions, such as oil / water emulsions, wetting agents, sterile solutions etc.

[0187] A composition comprising a non-radiolabeled compound in accordance with the invention, optionally in combination with a pharmaceutically acceptable excipient, can be provided e.g. as a precursor composition for a radiopharmaceutical composition. In a related aspect, the invention provides a kit comprising a non-radiolabeled compound in accordance with the invention which does not contain a radioactive component, optionally in combination with a pharmaceutically acceptable excipient, in combination with instructions for radiolabeling the compound.

[0188] In a related aspect, the compounds in accordance with the invention, such as the radiolabeled compounds in accordance with the invention, are provided for use as a medicament.

[0189] A compound in accordance with the invention, such as a radiolabeled compound, can be suitable for use in therapy or for use in diagnosis. Likewise, a pharmaceutical composition in accordance with the invention, such as a radiopharmaceutical composition, can be suitable for use in therapy (i.e. as a therapeutic composition) or for use in diagnosis (i.e. as a diagnostic composition).

[0190] Since compounds of the invention and pharmaceutical compositions in accordance with the invention can be used in a method of diagnosis, the invention provides as a further aspect a compound in accordance with the invention, such as a radiolabeled compound, or a pharmaceutical composition in accordance with the invention, such as a radiopharmaceutical composition, for use in a method of diagnosis in vivo of a disease or disorder. The method of diagnosis preferably involves nuclear diagnostic imaging, e.g. via Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT). For example, a radiolabeled compound in accordance with the invention wherein the fluorine atom attached to the silicon atom is [18F]fluorine is a preferred radiolabeled compound suitable for use in a method of diagnosis. As another example, reference can be made to a radiolabeled compound containing a complexed68Ga3+cation.

[0191] For example, the method of diagnosis may comprise administering a radiolabeled compound in accordance with the invention to a subject and detecting the compound in the subject, or monitoring the distribution of the compound in the subject, thereby detecting or monitoring the disease or disorder to be diagnosed. The subject may be a human or an animal and is preferably human. Alternatively, a method of diagnosis may also comprise adding a radiolabeled compound in accordance with the invention to a sample, e.g. a physiological sample obtained from a subject in vitro or ex vivo, and detecting the compound in the sample.

[0192] The method of diagnosis referred to above aims at the detection or the monitoring of a disease or disorder of the human or animal body. An example for a disease or disorder is cancer. It will be understood that the disease or disorder is typically one which is associated with the target structure of the targeting moiety RTcomprised by the compound in accordance with the invention used. For example, the presence or the increased presence of the target structure in the body of the subject may be indicative of the disease or disorder. In particular, target structures of interest, such as the ones discussed as examples above, may be overexpressed in a human disease, such as cancer.

[0193] Since compounds of the invention and pharmaceutical compositions in accordance with the invention can be used in therapy, i.e. in a method for the treatment of a disease or disorder, the invention provides as a as a further aspect a compound in accordance with the invention, such as a radiolabeled compound, or a pharmaceutical composition in accordance with the invention, such as a radiopharmaceutical composition, for use in a method of treatment of a disease or disorder. The method is preferably a method for the treatment of a disease or disorder via radioligand therapy. As an example for a radiolabeled compound in accordance with the invention useful in a method of treatment of a disease or disorder, reference can be made to a compound comprising a chelate group wherein the complexed metal cation is a177Lu cation or a90Y cation, preferably a177Lu cation.

[0194] For example, the method of treatment may comprise administering a radiolabeled compound or a radiopharmaceutical composition in accordance with the invention to a subject. The subject may be a human or an animal and is preferably human.

[0195] The method of treatment referred to above aims at the treatment of a disease or disorder of the human or animal body. An example for a disease or disorder is cancer. The disease or disorder is typically one which is associated with the target structure of the targeting moiety RTcomprised by the compound in accordance with the invention used.

[0196] It will be understood that suitability for a therapeutic and a diagnostic application is not mutually exclusive, i.e. a compound in accordance with the invention may be suitable for both applications. For example, a compound comprising a complexed177Lu cation can be used both for therapeutic and diagnostic imaging applications.

[0197] In particular, the compounds of the invention are suitable as radiohybrid (rh) ligands since they comprise a chelating group or chelate group together with a silicon-based fluoride acceptor group. For example, such a rh ligand can be alternatively radiolabeled with [18F]fluorine (e.g. for the purpose of PET diagnostic imaging) or a radioactive metal cation (such as a68Ga cation for PET, or a177Lu cation or90Y cation for radiotherapy). When a rh ligand is labeled with [18F]fluorine, a cold (non-radioactive) metal cation can be, but does not have to be complexed by the chelating group in the molecule, and when it is labeled with a corresponding radioactive metal cation, cold [19F] fluorine can be included. Therefore, the18F-labeled compound and the corresponding radiometal-labeled analog can possess the same chemical structure and thus identical in vitro and in vivo properties.

[0198] Thus, in line with this approach, the compounds in accordance with the invention include radiolabeled compounds wherein the silicon-based fluoride acceptor group is labeled with18F and a chelate group is present which contains a complexed non-radioactive metal cation (such as a cation ofnatLu,natGa, ornatY, preferably ofnatLu), and radiolabeled compounds wherein a chelate group is present and contains a complexed radioactive metal cation (such as a cation of177Lu,68Ga or90Y, preferably of177Lu) and the silicon-based fluoride acceptor group is not labeled with18F (thus carrying a19F).

[0199] Likewise, the invention provides the compounds in accordance with the invention for use in a hybrid method of diagnosis in vivo and therapy of a disease or disorder, which method comprises: as a step a), the administration of a compound in accordance with the invention wherein the fluorine atom attached to the silicon atom in the silicon-based fluoride acceptor group is18F and RCHis a chelating group which does not contain a complexed metal cation, or a chelate group which contains a complexed non-radioactive metal cation (such as a cation ofnatLu,natGa, ornatY, preferably ofnatLu), and, after step a), as a step b), the administration of a compound in accordance with the invention which is structurally identical to the compound administrated in step a), except that the fluorine atom attached to the silicon atom in the silicon-based fluoride acceptor group of the compound is19F (cold fluorine) and RCHis a chelate group which contains a complexed radioactive metal cation (such as a cation of177Lu,68Ga, or90Y, preferably177Lu).

[0200] In this specification, a number of documents including not only scientific journal articles but also patent applications and manufacturer’s manuals are cited (cf, e.g., the list of references in this respect). The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0201] The following examples further illustrate the invention as defined herein.

[0202] Examples

[0203] Synthesis of Fmoc-(SiFA)SeFe

[0204] The twelve step synthesis of (SiFA)SeFe starts with the meta bromination of isophthalic acid, a readily available and cheap starting material. After double esterification (ii) and reduction to the diol (iii) one hydroxyl group was selectively substituted by bromide (iv) to enable the introduction of the amine via a Staudinger reduction. The alcohol was THP protected (vi) against the laterfBu-Li reaction before reducing the azide (v) to the amide (vii). For the following harsh reaction conditions, the amine was protected with TMS (viii). The silicon center was introduced with an in situ umpolung withfBu-Li and subsequent aqueous workup deprotected the TMS groups (ix). A protection of the amine with the Fmoc-protection group for later application in solid phase peptide synthesis (SPPS) was performed. After THP deprotection (xi) the building block Fmoc-(SiFA)SeFe was synthesized by oxidation of the alcohol to the carboxylic acid (Figure 3).

[0205] 5-Bromoisophthalic acid (i)

[0206] For the aromatic bromination 50.0 g isophthalic acid (312.2 mmol, 1.0 eq.) and 53.6 g 1 ,3- Dibrom-5,5-dimethyl-hydantoin (187.3 mmol, 0.6 eq.) were solved in 300 mL concentrated H2SO4 and stirred for 3 h at 60 °C. After cooling down to RT, the orange emulsion was poured into ice and 100 mL 1 M HCI were added. The product was extracted with EtOAc (3 x 200 mL), the combined organic phases were washed with Brine (3 x 100 mL), dried with MgSCL and the solvent was removed under reduced pressure. The product was obtained as a colorless solid in quantitative yield.

[0207] 1H-NMR(400 MHz, DMSO-cfe): 6 8.41 (s, 1 H), 8.24 (s, 2H). Dimethyl 5-bromoisophthalate (ii)

[0208] The Esterification was performed by solving 5.0 g of i (20.5 mmol, 1.0 eq.) were in 82 mL MeOH and 4.1 mL H2SO4 and the solution was stirred at 70 °C for 16 h. After cooling to RT, the solvent was removed under reduced pressure and 100 mL H2O and 100 mL DCM were added. The crude product was extracted with DCM (3 x 100 mL) and the combined organic phases were washed with NaHCCh and Brine. The solution was dried via MgSCU and the solvent was removed under reduced pressure and after recrystallization from MeOH the product was obtained as colourless solid (3.89 g, 14.2 mmol, 86.9 %).

[0209] 1H NMR: (400 MHz, Chloroform-d) 5 8.60 (s, 1 H), 8.35 (s, 2H), 3.95 (s, 6 H).1H-NMR: (400 MHz, DMSO-cfe) 6 8.41 (s, 1 H), 8.30 (s, 2H), 3.90 (s, 6H).

[0210] Rf: 0.48 (10:1 , CH / EA).

[0211] (5-Bromo-1,3-phenylene)dimethanol (iii)

[0212] To a stirring solution of 3.4 g UAIH4 in 300 mL dry THF at O °C 24.4 g of ii (99.6 mmol, 1.0 eq.) solved in 100 mL dry THF were dropwise added. The slurry solution was stirred at RT for 16 h. The reaction was quenched by adding 400 mL H2O carefully. The solution was extracted with Et20 (3 x 200 mL), the combined organic phases were washed with brine and water, dried over MgSCU and the solvent was removed under reduced pressure. After flash purification (CH / EA = 1 :1 -> 100 % EA) the product was obtained as colourless needles (15.3 g, 70.5 mmol, 70.8 %).

[0213] 1H-NMR:1H NMR (400 MHz, DMSO-cfe) 6 7.35 (s, 2H), 7.24 (s, 1 H), 5.31 (s, 2H), 4.48 (s, 4H).

[0214] Rf: 0.56 (100% EA), 0.48 (1 :10, CH / EA), 0.18 (1 :1 , CH / EA)

[0215] (3-Bromo-5-(bromomethyl)phenyl)methanol (iv)

[0216] To 300 mL Toluene 40.0 g iii (184.3 mmol, 1.0 eq.) were added. Upon adding 25.0 mL HBr (48 wt% in H2O, 221.2 mmol, 1.2 eq.) the solids solved and the solution was stirred o.n. at 60 °C. After cooling to RT 100 mL NaHCCh were added. The mixture was extracted with Et20 (3 x 200 mL), the combined organic phases were dried over MgSCL and the solvent was removed under reduced pressure. After flash purification (100 % CH -> CH / EA = 1 :1) the product was obtained as a colourless solid (40.0 g, 142.9 mmol, 77.5 %).

[0217] 1H-NMR:1H NMR (400 MHz, Chloroform-d) 5 7.46 (s, 2H), 7.32 (s, 1 H), 4.69 (s, 2H), 4.43 (d, J = 2.9 Hz, 2H).

[0218] Rf: 0.64 (1 :1 , CH / EA). (3-(Azidomethyl)-5-bromophenyl)methanol (v)

[0219] To a solution of 26.04 g iv (92.9 mmol, 1.0 eq.) in 400 mL Aceton / H2O (v / v= 3:1) 12.07 g NalXh (185.8 mmol, 2.0 eq.) was added and the solution was stirred for 1 h at 60 °C. After complete conversion the volume was reduced by removing the acetone under reduced pressure. The residual solution was extracted with EtOAc (3 x 200 mL) and the combined organic phases were washed with brine (1 x 100 mL) and H2O (1 x 200 mL). After drying over NaSCL the solvent was removed under reduced pressure to obtain 22.5 g (92.9 mmol, 100 %) of an orange liquid as product.

[0220] 1H-NMR:1H NMR (500 MHz, Chloroform-d) 5 7.50 (s, 1 H), 7.39 (s, 1 H), 7.25 (s, 1 H), 4.70 (s, 2H), 4.33 (s, 2H).

[0221] Rf: 0.63 (1 :1 , CH / EA).

[0222] 2-((3-(Azidomethyl)-5-bromobenzyl)oxy)tetrahydro-2H-pyran (vi)

[0223] A solution of 25.0 g v (103.3 mmol, 1.0 eq.) and 18.7 mL Dihydropyran (206.5 mmol, 2.0 eq.) in 300 mL DCM was cooled to 0 °C and 2.0 g p-toluenesulfonic acid (10.3 mmol, 0.1 eq.) was added. The solution was stirred at RT for 1 h. It was added 100 mL brine to the solution and it was extracted with Et2O (3 x 100 mL) dried over NaSCL and the solvent and excessive Dihydropyran was removed under reduced pressure to obtain the product as 33.7 g (103.3 mmol, 100 %) of an orange oil.

[0224] 1H-NMR:1H NMR (500 MHz, Chloroform-d) 5 7.49 (s, 1 H), 7.38 (s, 1 H), 7.23 (s, 1 H), 4.76 (d, J = 12.5 Hz, 1 H), 4.70 (t, J = 3.5 Hz, 1 H), 4.48 (d, J = 12.5 Hz, 1 H), 4.33 (s, 2H), 3.60 - 3.51 (m, 2H), 1.92 - 1.71 (m, 6H).

[0225] Rf: 0.78 (1 :1 , CH / EA).

[0226] (3-Bromo-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)methanamine (vii)

[0227] In 300 mL of THF / H2O (v / v= 10 / 1) 30.2 g vi (92.7 mmol, 1.0 eq.) was solved. The solution was cooled to 0 °C and 29.2 g PPh2(111.2 mmol, 1.2 eq.) was added slowly under gas development. The solution was stirred at 70 °C for 1 h. The solvent was removed under reduced pressure and 100 mL 1 M NaOH was added to avoid ammonium ion formation. It was extracted with EtOAc (3 x 100 mL) dried over NaSO4 and the solvent was removed under reduced pressure. After 1 h the orange viscous oil solidified and the remaining triphenylphosphine oxide was filtered of by washing with pentane (20 x 50 mL). After removing the solvent under reduced pressure and purification via flash chromatography the product was obtained as 19.9 g (66.2 mmol, 71.4 %) of an orange oil.

[0228] 1H-NMR:1H NMR (400 MHz, Chloroform-d) 6 7.39 (s, 2H), 7.22 (s, 1 H), 4.74 (d, J = 12.3 Hz, 1 H), 4.70 (m, 1 H), 4.45 (d, J = 12.3 Hz, 1 H), 3.85 (s, 1 H), 3.59 - 3.39 (m, 1 H), 1.93 - 1.62 (m, 6H).

[0229] Rf: 0.40 (20:1 , DCM / MeOH).

[0230] N-(3-Bromo-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)benzyl)-1,1,1-trimethyl-N- (trimethylsilyl)silanamine (viii)

[0231] To a solution of 19.9 g vii (66.2 mmol, 1.0 eq.) in 400 mL dry DCM 20.18 mL triethylamine (145.6 mmol, 2.2 eq.) was added. After cooling to 0 °C 16.8 mL trimethylsilyl chloride (132.3 mmol, 2.0 eq.) was added dropwise under precipitation of a colorless solid. The solution was stirred o.n. at RT. The solvent and the excessive TMSCI were removed under reduced pressure and the product was extracted with dry hexane (5 x 100 mL). After removing the solvent under reduced pressure the product was obtained as 22.9 g of an orange oil (51.5 mmol, 77.9 %).

[0232] 1H-NMR:1H NMR (500 MHz, Chloroform-d) 5 7.31 (s, 1 H), 7.30 (s, 1 H), 7.19 (s, 1 H), 4.74 (d, J = 12.4 Hz, 1 H), 4.70 (t, J = 3.6 Hz, 1 H), 4.44 (d, J = 12.4 Hz, 1 H), 4.07 (s, 2H), 3.57 - 3.53 (m, 2H), 1.91 - 1.72 (m, 6H), 0.08 (s, 18H).

[0233] (3-(Di-tert-butylfluorosilyl)-5-(((tetrahydro-2H-pyran-2yl)oxy)methyl)phenyl) methanamine (ix)

[0234] For introduction of the silicon center 10.7 g viii (24.1 mmol, 1.0 eq.) were solved in 200 mL dry THF and 31.1 mLfBuLi (53.0mmol, 1.6 M in hexane, 2.2 eq.) was added dropwise at -78 °C. The solution was stirred for 15 min at -78 °C and was then added dropwise to a stirring solution of 5.9 mLfBu2SiF2 (26.5 mmol, 1.1 eq.) at -78 °C. The solution was stirred o.n. at RT before adding 200 mL brine and adjust the pH to 8-9 with NaOH. The organic solvent was removed under reduced pressure and it was extracted with Et20 (3 x 100 mL), dried over NaSCL and the solvent was removed under reduced pressure. The crude product was purified via flash chromatography to obtain the product as 4.2 g (11.0 mmol, 45.8 %) of a yellow solid.

[0235] 1H-NMR:1H NMR (400 MHz, Chloroform-d) 5 7.46 (s, 1 H), 7.44 (s, 1 H), 7.38 (s, 1 H), 4.81 (d, J = 12.1 Hz, 1 H), 4.75 - 4.67 (m, 1 H), 4.52 (d, J = 10.8 Hz, 1 H), 3.89 (s, 2H), 3.57 - 3.52 (m, 2H), 1 .88 - 1 .79 (m, 6H), 1 .06 (s, 18H).

[0236] Rf: 0.80 (10:1 , DCM / MeOH). (9H-Fluoren-9-yl)methyl-(3-(di-tert-butylfluorosilyl)-5-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)benzyl)carbamate (x)

[0237] For Fmoc protection 4.5 g ix (11 .9 mmol, 1 .0 eq.) was solved in 50 ml iPrOH and the pH was adjusted to pH 9 with triethylamine. At 0 °C a solution of 3.7 g fluorenylmethyloxycarbonyl chloride (14.3 mmol, 1.2 eq.) in 10 mL THF was added and stirred for 30 min at RT. The solvent was removed under reduced pressure and 50 mL brine was added. The solution was extracted with Et20 (3 x 100 mL), dried over NaSCL and the solvent was removed under reduced pressure. The crude product was purified via flash chromatography to obtain the product as 3.1 g (5.1 mmol, 42.7 %) of a yellow solid.

[0238] 1H-NMR:1H NMR (500 MHz, Chloroform-d) 5 7.77 (t, J = 7.7 Hz, 2H), 7.64 - 7.60 (m, 2H), 7.51 (s, 1 H), 7.44 (s, 1 H), 7.42 - 7.39 (m, 2H), 7.36 (s, 1 H), 7.32 - 7.30 (m, 2H), 4.81 (d, J = 12.2 Hz, 1 H), 4.72 - 4.69 (m, 1 H), 4.52 (d, J = 12.4 Hz, 1 H), 4.44 (s, 2H), 4.43 (s, 2H), 4.24 (t, J = 7.0 Hz, 1 H), 3.57 - 3.46 (m, 1 H), 1.90 - 1.65 (m, OH), 1 .05 (s, 4H).

[0239] Rf: 0.22 (5:1 , CH / EA).

[0240] (9H-Fluoren-9-yl)methyl-(3-(di-tert-butylfluorosilyl)-5-(hydroxymethyl)benzyl)carbamate (xi)

[0241] For TH P deprotection 3.1g of x (5.1 mmol, 1.0 eq.) was solved in 25 mL THF and 25 mL MeOH and 25 mL 1 M HCI was added. After stirring 30 min at RT 50 mL NaHCCh was added. The solution was extracted with DCM (3 x 100 mL), dried over NaSCL and the solvent was removed under reduced pressure. The crude product was purified via flash chromatography to obtain the product as 890 mg (1.7 mmol, 33.5 %) of a yellow solid.

[0242] 1H-NMR:1H NMR (500 MHz, Chloroform-d) 5 7.76 (d, J = 7.6 Hz, 2H), 7.60 (d, J= 7.5 Hz, 2H), 7.50 (s, 1 H), 7.44 (s, 1 H), 7.40 (t, J = 7.5 Hz, 2H), 7.37 (s, 1 H), 7.31 (t, J = 7.4 Hz, 2H), 4.71 (s, 2H), 4.44 (m, 4H), 4.24 (t, J = 6.9 Hz, 1 H), 1 .05 (s, 18H).

[0243] Rf: 0.58 (1 :1 , CH / EA).

[0244] 3-(((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)methyl)-5-(di-tert-butylfluorosilyl) benzoic acid ((SiFA)SeFe)

[0245] For the oxidation from alcohol to acid 890 mg of xi (1.7 mmol, 1.0eq.) and 54.1 mg TEMPO (350.0 pmol, 0.2 eq.) were solved in 20 mL ACN. Then 10 mL of Phosphate buffer (pH 6.7) was added, heated to 40 °C and 391 .2 mg NaCIO2 (3.5 mmol, 2.0 eq.) solved in 5 mL H2O and 352.0 pL NaOCI (350.0 pmol, 6 % in H2O, 0.2 eq.) were added simultaneously over 1 h. After stirring at 40 °C o.n. the solution was extracted with Et20 (3 x 50 mL), dried over NaSC>4 and the solvent was removed under reduced pressure. The crude product was purified via flash chromatography to obtain the product as 716 mg (1.3 mmol, 69.8 %) of a yellow solid.

[0246] 1H-NMR:1H NMR (500 MHz, Chloroform-d) 5 8.25 (s, 1 H), 8.09 (s, 1 H), 7.79 (s, 1 H), 7.76 (d, J = 7.7 Hz, 2H), 7.60 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 4.52 - 4.43 (m, 4H), 4.25 (t, J = 6.9 Hz, 1 H), 1.06 (s, 18H).

[0247] 19F-NMR: (400 MHz, Chloroform-d) 5 -188.18.

[0248] 29Si-INEPT NMR: (79 MHz, Chloroform-d) 5 11.98 (d,3J(29Si-1H) = 8.2 Hz).

[0249] Rf: 0.40 (1 :1 , CH / EA + 0.1 % AcOH).

[0250] SSTR2-targeted radiohybrid compound

[0251] Synthesis of (SiFA)SeFe-rhTATE4

[0252] To generate (SiFA)SeFe-rhTATE4 (Figure 2) the rh-concept was applied to a TATE analog containing the SiFA building block (SiFA)SeFe for18F-labeling and a DOTA chelator for177Lu-labeling. The SiFA building block (SiFA)SeFe was incorporated at a bridged position on the pharmacophore coupled linker Fmoc-ChOc-OH. Subsequently with the amino acid Fmoc- D-Asp-OfBu as a linker the chelator DOTA was bound terminally.

[0253] • Synthesis of ( SiFA ) SeFe-rh TA TE4

[0254] The synthesis of (SiFA)SeFe-rhTATE4 is carried out on resin using the general working procedures (GS). The resin-bound synthesis of H-TATE(PG)-2-CT (GS8) is followed by the coupling of Fmoc-O2Oc-OH (GS3), Fmoc-(SiFA)SeFe-OH (GS3), Fmoc-D-Asp-OfBu (GS3) and DOTA(fBu)a (GS3). Before the coupling of the next amino acid in each case, the N- terminus is Fmoc-deprotected (GS4). After resin cleavage, removal of all protecting groups (GS7) and purification by RP-HPLC (30-50% MeCN / H2O with 0.1 % TFA, v / v, 30 min, A = 220 nm), 4.08 mg (2.05 mol, 3%) is obtained in the form of a white solid.

[0255] MS (ESI positive): m / z calculated for [natLu]Lu-(SiFA)SeFe-rhTATE4: 2159.8, found: 1081.0 [M + 2H+]2+. • Synthesis of DOTA-TATE

[0256] The resin-bound synthesis of H-TATE(PG)-2-CT (GS8) is followed by the coupling of DOTA(tBu)3 (GS3). After resin cleavage, removal of all protecting groups (GS7) and purification by RP-HPLC (15-40% MeCN / H2O with 0.1 % TFA, v / v, 30 min, A = 220 nm), 1.11 mg (7.73 mol, 19%) DOTA-TATE is obtained in the form of a white solid.

[0257] • Synthesis Si F Al in- TATE

[0258] The resin-bound synthesis of H-TATE(PG)-2-CT (GS8) is followed by the coupling of Fmoc-O2Oc-OH (GS3), Fmoc-L-Asp(OfBu)-OH (GS3), Fmoc-L-Asp(OfBu)-OH (GS2), Fmoc-Asn(Ac3AcNH- ?-Glc)-OH (GS3) and b / s-Boc-amino-oxyacetic acid (GS3). Before the coupling of the next amino acid in each case, the / V-terminus is Fmoc-deprotected (GS4). After resin cleavage, removal of all protecting groups (GS7) and acetyl deprotection (GS5), purification is carried out by RP-HPLC (30-35% MeCN / H2O with 0.1 % TFA, v / v, 20 min, A = 220 nm).

[0259] Oximligation: 1.0 eq. TATE-O2OC-i-Asp-L-Asp-Asn-amino-oxy-acid and 4.0 eq. SiFAIin aldehyde in 400 pL phosphate buffer / MeCN (1 / 1 , v / v) are vesified with 4 N NaOH solution until a pH of pH = 4 is established. After 20 min the solution is diluted 1 / 1 with H2O (+0.1% TFA) and purified by RP-HPLC (20-45-60% MeCN / H2O with 0.1 % TFA, v / v, 10-30 min, A = 220 nm), 3.41 mg (1 .52 mol, 5%) is obtained in the form of a white solid.

[0260] GS1: Loading of the 2-CTC resin

[0261] The 2-chloro-tritylchlorid (2-CTC) resin (loading density: 1.6 mmol / g) was swollen for 30 min in 5 mL NMP and then washed with DMF (6 x 5 mL). The resin was loaded with an Fmoc protected amino acid (AA) using Fmoc-AA-OH (1.5 eq.) and DIPEA ( / V, / V-Diisopropylethylamine) (1.5 eq.) in DMF ( / V, / V-Dimethylformamide) in a 20 mL peptide syringe. After 15 min of pre-activation at room temperature, another 3.0 eq. of DI PEA was added and the mixture was shaken at room temperature for 2 h. MeOH (1 mL / g resin) was added to the resin and shaken for 15 minutes. Afterwards, the resin was washed five times each with DMF (5 mL), MeOH (5 mL) and DCM (5 mL) and dried in a desiccator.

[0262] GS2: Standard peptide coupling to the resin

[0263] The loaded resin is swollen in NMP for 30 min, washed six times with DMF (5 mL), and N- terminally Fmoc deprotected. Prior to coupling at the C-terminus of side-chain-protected Fmoc- AA-OH (1.5 eq.), preactivation is performed with TBTU (1.5 eq.), HOAt (1.5 eq.), and DIPEA (4.0 eq.) in 5 mL DMF. After 10 min, the activated solution is added to the resin-bound peptide containing the free amine (2-CTC-AA-NH2) and shaken for 1.5 h at room temperature. The resin is then washed six times with DMF (5 mL) and, after Fmoc deprotection, washed another six times with DMF (5 mL). Now the next amino acid can be reacted, or washed six times with DCM and dried in a desiccator.

[0264] GS3: Deviating peptide coupling to the resin

[0265] After swelling the resin in NMP for 30 min and washing with DMF (6x 5 mL), the respective substrate is coupled to the resin-bound peptide (Table 1). The resin is then washed six times with DMF (5 mL).

[0266] Table 1 : Deviating equivalents, coupling reagents, base (DIPEA), preactivation times, and reaction times for coupling the respective substrates to the resin-bound peptide (1.0 eq.).

[0267] GS4: Fmoc deprotection

[0268] / V-terminal Fmoc-protected amino acids or peptides bound to the resin are deprotected by adding 20% piperidine in DMF (5 mL). The deprotection reagent is added twice (1 x5 min, 1 x15 min). The resin is then washed with DMF (6x with 5 mL each).

[0269] GS5: Acetyl deprotection

[0270] Acetyl deprotection is performed by dissolving 50 pmol of the peptide in MeOH and adding NaOMe until the pH is 11-12. After 15 min, the reaction is stopped by adding TFA (pH = 2).

[0271] GS6: Cleavage from the resin with retention of acid labile protective groups

[0272] The peptide bound to the resin is mixed with 5 mL of 2,2,2-Trifluorethanol (TFE) / DCM / AcOH (3 / 6 / 1) and agitated for 20 min at room temperature. The solution with the protected peptide is collected and then evaporated under a nitrogen stream. GS7: Cleavage from the resin with removal of acid labile protection groups

[0273] The peptide bound to the resin is mixed with 5 mL of TFA / TIPS / H2O (95 / 2.5 / 2.5) and agitated two times for 45 min at room temperature. The solution with the deprotected peptide is collected in a 50 mL round-bottom flask and the remaining resin is washed once with 5 mL TFA and stirred overnight. The following day, the TFA is evaporated under nitrogen stream.

[0274] GS8: Synthesis of the binding motif TATE on resin with protecting groups (PG) (H-TATE(PG)-2-CT)

[0275] The synthesis of H-TATE(PG)-2-CT is carried out on the resin using the general working procedures (GS). 2-CTC resin is loaded with Fmoc-L-Thr(fBu)-OH (GS1). This is followed by the coupling of Fmoc-L-Cys(Acm)-OH, Fmoc-L-Thr(fBu)-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc- / _-Tyr(fBu)-OH, Fmoc-L-Cys(Acm)-OH and Fmoc-D-Phe-OH (GS2). Before the coupling of the next amino acid in each case, the / V-terminus is Fmoc-deprotected (GS4). The final amino acid is only deprotected after the formation of the disulfide bridge.

[0276] Formation of the disulfide bridge

[0277] Fmoc-D-Phe-L-Cys(Acm)-L-Tyr(tBu)-D-Trp(Boc)-L-Lys(Boc)-L-Thr(fBu)-L-Cys(Acm)-L-Thr(fBu)- 2-CT (1.0 eq.) is mixed with TI(TFA)a (4.0 eq.) and glycerol (4.0 eq.) in DMF (8 mL / g resin). After 1 h at room temperature, the solution is discarded and a fresh solution of the reaction solution is added to the resin for another 1 h at room temperature. The resin is then washed with DMF (6 x 5 mL / g resin). Test cleavage from the resin with retention of acid labile protective groups is used to verify the completeness of the cyclization (GS6). Characterization is investigated by analytical RP-HPLC and ESI-MS. After final Fmoc deprotection, the product, H-D-Phe-cyclo[L-Cys-L-Tyr(fBu)-D-Trp(Boc)-L-Lys(Boc)-L-Thr(fBu)-L-Cys]-L-Thr(fBu)-2-CT is present bound to the resin.

[0278] RP-HPLC (10-90% MeCN / H2O with 0.1 % TFA, v / v, 15 min, A = 220 nm) for H-TATE(PG)-OH: fR= 13.4 min.

[0279] MS (ESI positive): m / z calculated for H-TATE(PG)-OH: 1416.7; found: 1418.3 [M + H+]+.

[0280] • Synthesis of cold metal complexes

[0281] Complexation withnatLu-luthetium For the incorporation ofnatLu-luthetium, LuCh (20 mM in H2O, 3.0 eq.) is added to a 2 mM solution of the compound in DMSO and diluted to 1 mM by addition of DMSO. The obtained solution is incubated at 80°C for 15 min.

[0282] RP-HPLC (10-60% MeCN / H2O with 0.1 % TFA, v / v, 15 min, A = 220 nm) for [natLu]Lu- (SiFA)SeFe-rhTATE4: fR= 13.0 min.

[0283] MS (ESI positive): m / z calculated for [natLu]Lu-DOTA-TATE: 1606.5, found: 804.6 [M + 2H+]2+.

[0284] • Radiolabeling

[0285] Fluorine-18 labeling

[0286] For [18F]-labeling, the aq. [18F]fluorine (120 MBq) is retained on a SAX cartridge (Sep-Pak Accel Plus QMA Carbonate Plus Light, 46 mg, Waters) preconditioned with 10 mL H2O. The cartridge is dried with air (10 mL), then washed slowly with dry DMSO (8 mL) and dried again with air (10 mL). The dried fluorine-18 is eluted with 500 pL ammonium formate (40.0 mg in 500 pL dry DMSO) into a 1.5 mL reaction tube (Protein LowBind, Eppendorf®). The reaction takes places by adding 30 pL (30 nmol) of the ligand (1 mM strain in DMSO) at 40°C for 5 min. The reaction is stopped by adding 10 mL of PBS pH = 3 (pH = 3 adjusted with 1 M aq. HCI). The solution is then slowly loaded onto an Oasis HLB Plus Light cartridge (30 mg sorbent, 30 pm particle size) preconditioned with abs. EtOH (10 mL) and H2O (10 mL). The cartridge is washed with PBS pH = 7.4 (10 mL) and then dried with air (10 mL). The18F-labeled ligand is eluted using an elution cocktail of abs. EtOH and PBS pH = 7.4 (7 / 3 v / v; 300 pL). Quality controls are performed by analytical radio-RP-HPLC (MeCN / H2O: 10-60% with 0.1 % TFA in 15 min) and radio-thin layer chromatography (flow agent: 60% MeCN / 40% PBS (6 / 4 v / v) with 10% NaOAc in H2O (2 M) and 1 % TFA, stationary phase: TLC Silica gel 60 F254 from Merck Millipore).

[0287] Luthetium-177 labeling

[0288] For luthetium-177 labeling, the aq. [177Lu]LuCl3 (30 MBq) is added to 1 pL (1 nmol) of the ligand (1 mM stock in DMSO), 10 pL of a NaOAc buffer (pH = 5.5), 22 pL 0.04 M HCI and reacted at 70°C for 5 min. lodine-125 labeling

[0289] [^IJI-TOC

[0290] For in vitro studies ( / C50, n = 3), 50-150 pg of TOC are dissolved in 20 pL of DMSO and 280 pL of TRIS buffer (25 mM TRIS-HCI, 0.4 mM NaCI, pH = 7.5) in a 1.5 mL Eppendorf reaction tube (Protein LowBind). The solution is transferred to another reaction tube (1.5 mL, Protein LowBind) coated with lodogen® (150 g) and 5.00 pL of (10 - 20 MBq) [125l]Nal (74 TBq, 40 mM NaOH, HARTMANN ANALYTIC GmbH (Braunschweig, Germany)) is added. After 15 min at room temperature, the reaction is stopped by separation from the oxidant (lodogen®) and the crude product is purified by analytical RP-HPLC [(20-40% in 15 min): fR= 5.1 min], 10 vol% Na-ascorbate solution (100 mM in H2O, radiolysis quencher) is added to the resulting product solution. The concentration of [125I]I-TOC is determined volumetrically by transferring the solution to a new vessel (20 mL reaction vessel) and the amount of [125I]I-TOC contained is measured using an activimeter. The product obtained has a radiochemical yield of RCY (radio-RP-HPLC) = 42.9% and a radiochemical purity of RCP (radio-RP-HPLC) > 99%. Analysis of [125I]I-TOC was performed by co-injection of [natl]l-TOC using a radio-RP-HPLC. [125I]I-TOC is stored at -4 °C and can be used for up to three weeks.

[0291] Radio-RP-HPLC (20-50% MeCN / H2O with 0.1 % TFA, v / v, 20 min): fR= 5.1 min.

[0292] Table 2: Results of18F- / 177Lu-labeling reporting radiochemical conversation (RCC), radiochemical yield decay corrected (RCYd.c), radiochemical purity via radio-RP-HPLC (RCPHPLC) and radiochemical purity via radio-TLC (RCPTLC).

[0293] In vitro Evaluation

[0294] [nat / i8p][nat / i 77|_u] |_u_(gi p^gepe- r|-l-|-^-|-^4wasevaluated in in vitro experiments and compared with the clinical standards [nat / 18F]SiFA / / n-TATE and [nat / 177Lu]Lu-DOTA-TATE. The studies included determination of binding affinity to sstR2-expressing CHOsst2 cells, lipophilicity, human serum albumin binding, and human serum stability (18F-labelled: 1 h incubation time for diagnostic applications,177Lu-labeled: 24 h incubation time for therapeutic applications) (Table 3). To test the chemical identity of the theranostic compound, the lipophilicity was determined for both the18F- and the177Lu-labeled species. The value for the stability of [18F]SiFA / / n-TATE was taken from the literature.43 Cell culture

[0295] AR42J cells (CLS GmbH, Eppelheim, Germany and Sigma Aldrich, Gillingham, UK) were cultured in RPMI medium (10% FBS + 2.5Vol% L-GIn solution (200 mM) + 1Vol% MEM non-essential amino acid solution, v / v) at 37°C in a humidified 5% CO2 atmosphere. To ensure uniform cell growth, they are passaged at approximately 80% confluence (2 - 4 days). The culture medium is removed and the remaining cell lawn washed with PBS (6 mL, 37°C). By treatment with EDTA (0.1%) in PBS (5 mL, 5 min, 37°C) at 37°C, the cells are detached from the bottom of the cell culture flask and suspended after addition of 5 mL RPMI medium (10% FBS + 2.5Vol% L-GIn solution (200 mM) + 1 Vol% MEM non-essential amino acid solution, v / v). Centrifuge the suspension (1.300 rpm, 3 min, RT) and resuspend the cell pellet in fresh RPMI medium (10% FBS + 2.5Vol% L-GIn solution (200 mM) + 1 Vol% MEM non-essential amino acid solution, v / v). A portion of the suspension is transferred to new culture flasks and the volume is made up to 25 mL with RPMI medium (10% FBS + 2.5 Vol% L-GIn solution (200 mM) + 1 Vol% MEM non-essential amino acid solution, v / v). Cells are then stored at stated incubation conditions and cell density is checked regularly under an inverted microscope.

[0296] Culture the adherent SST2-transfected CHOsst2 cells (Chinese hamster ovary (CHO) cells stably transfected with human sst2R (epitope-tagged at the / V-terminal end), provided by Dr. Jenny Koenig, University of Cambridge, Cambridge, United Kingdom) were cultured in DMEM / F12 GlutaMax medium (plus 10% FBS v / v) at 37°C in a humidified 5% CO2 atmosphere. To ensure uniform cell growth, they are passaged at approximately 80% confluence (2 - 4 days). The spent medium is removed and the remaining cell lawn washed with PBS (10 mL, 37°C). By treatment with trypsin / EDTA (5 mL, 5 min, 37°C) at 37°C, the cells are detached from the bottom of the cell culture flask and suspended after addition of 5 mL DMEM / F12 GlutaMax medium (plus 10% FBS v / v). Centrifuge the suspension (1.300 rpm, 3 min, RT) and resuspend the cell pellet in fresh DMEM / F12 GlutaMax medium (20 mL, plus 10% TCS v / v, 37°C). A portion of the suspension is transferred to new culture flasks and the volume is made up to 25 mL with DMEM / F12 GlutaMax medium (plus 10% FBS v / v). Cells are then stored at stated incubation conditions and cell density is checked regularly under an inverted microscope.

[0297] Binding affinity (IC50)

[0298] In vitro competition studies were performed on CHOsst2 cells (Chinese hamster ovary (CHO) cells stably transfected with human sst2R (epitope-tagged at the / V-terminal end), provided by Dr. Jenny Koenig, University of Cambridge, Cambridge, United Kingdom), which were seeded (24-well plates, 1.0 x 105cells / well, DMEM / F12 GlutaMax plus 10% FCS) and incubated at 37°C for 24 ± 2 h before the experiment. On the day of the experiment, the DMEM / F12 GlutaMax medium (plus 10% FCS) was removed and each well was washed with 300 pL of HBSS (supplemented with 1 vol-% of bovine serum albumin, = HBSA). After the addition of 200 pL of HBSA, 25 pL / well of HBSA (control, n = 3) or the respective ligand in concentrations ranging from 10'10to 10'4M (n = 3) was added. Subsequently, 25 pL of the radiolabeled reference [125I]I-TOC (1 nM in HBSA, for synthesis and characterization see Supplemental Information) was added to each well. After incubation at room temperature for 1 h, the supernatant was removed, washed with ice-cold PBS (300 pL), and the washing solutions were combined with the supernatants. The cells were lysed by adding NaOH (300 pL, 1 M). The cell lysate is removed after incubation at room temperature for 20 min and washed with NaOH (300 pL, 1 M), while both NaOH-containing fractions were combined. Subsequently, the activities of both the supernatant and the lysate were measured separately in a y-counter and the / C50 value was calculated using GraphPad Prism software (GraphPad Prism 4.0 Software Inc., La Jolla, California, USA).

[0299] Lipophilicity (logDpH=7.4)

[0300] For the determination of the octanol-PBS partition coefficient (logDPH=7.4 values), 500 pL 1- octanol and 500 pL PBS (pH = 7.4) are added to a 1.5 mL reaction tube (Eppendorf Tube®) (n = 6). Add 0.5 MBq each of the labeled component and vortex for 3 min. After centrifugation (9.000 rpm, 5 min, room temperature), 100 pL of the octanol phase and 100 pL of the PBS phase are taken and quantified by y-counter. The experiment is repeated at least 6 times.

[0301] Binding to human serum albumin (HSA)

[0302] HSA binding studies were performed according to a previously published procedure, using RP-HPLC and HSA which is solid-phase fixed on a Chiralpak HSA column (50 x 3 mm, 5 pm, H13 h-2433, Daicel, Tokio, Japan).54A flow rate of 0.5 mL / min at room temperature was used. A freshly prepared 50 mM aqueous solution of NH4OAC (pH 6.9) was used as mobile phase A, and isopropanol (HPLC grade, VWR, Germany) was used as mobile phase B. A gradient of 100% A (0 to 3 min) followed by 80% A (3 to 40 min) was used for the experiments. Before the analysis of all compounds, the column was calibrated with nine reference substances having HSA binding known from the literature in the range of 13 to 99% (see Table 7).54’55All compounds, were prepared in a 1 / 1 mixture (v / v) of isopropanol and a 50 mM aqueous solution of NH4OAC (pH 6.9) at a final concentration of 0.5 mg / ml.

[0303] Stability studies in human serum

[0304] 5 MBq of the respective labeled compound was added to 200 pL of human serum (from a healthy volunteer) and incubated at 37°C for 1 h. After the addition of 50 vol% of cold ethanol and 150 vol% of cold MeCN, centrifugation was performed at 13.000 rpm for 20 min. The supernatant was decanted and centrifuged at 13.000 rpm for 10 min in a centrifuge tube with a 0.45 pm cellulose acetate filter. The filtrate is injected into a Radio-RP-HPLC and the number of intact radioligand is quantified.

[0305] Table 3: Summary of in vitro evaluations collected, which include binding affinity (IC50, n=3), lipophilicity (logOPh7.4, n=6), human serum albumin binding (HSA, n=1) and stability studies in human serum (% intact tracer, n=3) after 1 h (18F-labeled, excepted of [177Lu]Lu- DOTA-TATE) and 24 h (177Lu-labeled) incubation at 37°C.

[0306] [natLu]Lu-(SiFA)SeFe-rhTATE4 shows a binding affinity in the low nanomolar range and thus, demonstrate the effectiveness of the selected linker sequence Fmoc-ChOc-OH for affinity retention. While the reference compounds [natLu]Lu-DOTA-TATE and SiFA / / n-TATE exhibit very similar / C50 values of 7.24 ± 0.91 nM and 7.46 ± 1.40 nM, respectively, the compound [natLu]Lu-(SiFA)SeFe-rhTATE4 shows a slightly lower, but still extremely promising value of 9.32 ± 0.49 nM. The reference [177Lu]Lu-DOTA-TATE is the most hydrophilic compound (logOPH=7.4: -3.70 ± 0.05) of the series. In direct comparison, the compound [177Lu]Lu- (SiFA)SeFe-rhTATE4 (logDPH=7.4: -1.70 ± 0.06) shows a slightly more hydrophilic character than the reference [18F]SiFA / / n-TATE (logDpH=7.4: -1-41 ± 0.07).

[0307] Regarding binding to HSA, [natLu]Lu-DOTA-TATE shows the lowest binding at 51 %. While SiFA / / n-TATE has an HSA binding of 92%, the radiohybrid [natLu]Lu-(SiFA)SeFe-rhTATE4 shows comparable HSA binding of 95%. With regard to diagnostic application, the18F-labeled radiohybrid, like the diagnostic reference [18F]SiFA / / n-TATE (98 ± 3.0% intact tracer43), shows no degradation after 1 hour incubation in human serum ( 99% intact tracer). For the therapeutic applicability, [177Lu]Lu-(SiFA)SeFe-rhTATE4 (91 ± 2.0% intact tracer) has a high stability after 24 h of incubation comparable to the reference ligand [177Lu]Lu-DOTA-TATE (98 ± 3% intact tracer). In vivo Evaluation

[0308] Animal experiments were performed by certified personnel following a previously published method.56Experiments were performed in agreement with the general animal welfare regulations in Germany (German Animal Welfare Act, as published on May 18, 2006, as amended by Article 280 of June 19, 2020, permit no. ROB-55.2-2532.Vet_02-18-109 by the General Directorate of Upper Bavaria) and institutional guidelines for the care and use of animals. Specifically, female CD1-nu / nu mice aged 5-6 weeks (Charles River Laboratories International Inc., Sulzfeld, Germany) were acclimated in the in-house animal facility for one week prior to inoculation. Tumor xenografts were generated using AR42J cells (7.0 x 106cells per 200 pL) suspended in a 1 / 1 mixture (v / v) of RPMI 1640 medium and Cultrex® Basement Membrane Matrix Type 3 (Trevigen, Gaithersburg, MD, USA). This suspension was inoculated subcutaneously onto the right shoulder and animals were used when tumor volume was >100 mm3(1-2 week after inoculation). Exclusion criteria for animals from an experiment were either weight loss greater than 20%, tumor size greater than 1500 mm3, tumor ulceration, respiratory distress, or behavioral change. None of these criteria applied to any of the animals from the trial. No randomized or blinded approach was used in the allocation of the experiments. Health status is SPF according to the FELASA recommendation. Biodistribution studies (n = 3 - 5) were performed after 1 h p.i. For all labeled compounds, approximately 2-3 MBq (300 pmol) were administered. Collected data were statistically analyzed using Excel (Microsoft Corporation, Redmond, WA, USA) and OriginPro software (version 9.7) from OriginLab Corporation (Northampton, MA, USA).

[0309] Diagnostic applicability

[0310] The imaging capability of the new rh-compound was analyzed first by18F-labeling recording the biodistribution in AR42J tumor-bearing CD1-nu / nu mice after 1 h post injection (p.i.) (Table 4, Figure 4).

[0311] The biodistribution data of [18F][natLu]Lu-(SiFA)SeFe-rhTATE4 show low uptake in non-specific tissues (heart, spleen, intestine, muscle, bone with and without marrow: 0.34-5.47%ID / g). However, there was increased activity enrichment in the blood (4.88 ± 0.23%ID / g) and in the well-perfused lungs (6.87 ± 0.21 %l D / g), as well as the liver (5.47 ± 0.47%ID / g). Interestingly, uptake in sstR2-specific organs (pancreas: 11.65 ± 0.51 %l D / g, stomach: 10.63 ± 0.99%l D / g), and accumulation in the kidneys (26.88 ± 1 ,49%ID / g) is observed, which suggests primarily renal excretion. Most notably, [18F][natLu]Lu-(SiFA)SeFe-rhTATE4 also features a remarkably high tumor uptake of 53.58 ± 5.51 %l D / g. For a more precise assessment of the imaging quality, the tumor to background values are used (Table 5).

[0312] [18F][natLu]Lu-(SiFA)SeFe-rhTATE4 shows high tumor-to-organ ratios for the lung (7.37 ± 0.97), the spleen (40.13 ± 4.45), the pancreas (4.54 ± 0.54), intestine (21.31 ± 3.54), adrenal glands (17.33 ± 1.73) and especially the bone with (31.61 ± 6.12) and without marrow (77.52 ± 27.54). The tumor-to-organ ratio of the lung (7.37 ± 0.97), liver (9.09 ± 1.73), and stomach (4.86 ± 0.26) rated as sufficient for PET imaging. Only the kidney (1.85 ± 0.26) and blood (10.87 ±0 .78) have a low tumor-to-organ ratio. Due to the good imaging properties of [18F][natLu]Lu-(SiFA)SeFe-rhTATE4, competition studies with [natGa]Ga-DOTA-TATE (40 nmol) were carried out to determine the specificity (Table 4, Figure 5).

[0313] The specific uptake in the tumor, stomach and pancreas could be determined by the competitive study with [natGa]Ga-DOTA-TATE due to the reduced uptake (tumor = 1 ,96%ID / g, pancreas = 0.75%ID / g, stomach = 2.50 % I D / g). No reduction can be observed for the lung, intestine and adrenal glands. For these distinct organs binding to other sstR-types might be questionable. Non-specific uptake of [18F][natLu]Lu-(SiFA)SeFe-rhTATE4 could be also observed for all other organs (heart, spleen, kidneys, etc.). In particular, for the kidneys, it could be clarified that [18F][natLu]Lu-(SiFA)SeFe-rhTATE4 uptake is clearly unspecific, i.e. not sst2 mediated. The comparably high renal activity accumulation during co-incubation is presumed to originate from receptor saturation by the cold competitor resulting in an elevated excretion rate of the radioligand.

[0314] Therapeutic applicability

[0315] For the evaluation of the chemical identity in vivo, the compound (SiFA)SeFe-rhTATE4 was further177Lu-labeled and evaluated after 1 h p.i. in AR42J tumor-bearing CD1-nu / nu mice (Table 4, Figure 6).

[0316] The biodistribution data show different absolute values of the18F and177Lu-labeled (SiFA)SeFe-rhTATE4 for the kidney (26.88 ± 1 ,49%ID / g vs. 14.80 ± 1 ,95%ID / g, respectively) and the tumor (53.58 ± 5.51 %l D / g vs. 32.15 ± 8.55%ID / g). However, the biodistribution trend is generally maintained, also with respect the other organs, which indicates a comparable in vivo performance and thus, chemically identical compounds.

[0317] Due to the slow blood clearance within the evaluations after 1 h p.i., biodistribution data were also collected after 6 h p.i. in AR42J tumor-bearing CD1-nu / nu mice with lutetium-177 (Table 4). After 6 h p.i., a clearance from the non-tumor-tissues (with values of 0.07 - 5.08%ID / g) can be observed. It is striking that the accumulation of activity in the tumor has only decreased by approx. 30% (22.97 ± 12.04%ID / g after 1 h vs 32.15 ± 8.55%ID / g after 6 h). This indicates for a high radiation dose to be deposited in the sst2 positive primary tumor and metastases with a low radiation burden for other organs at 6 h p.i. and hence, a considerable therapeutic effect with minimized detriment for non-tumorous tissue.

[0318] Since the longest possible therapeutic effect is desired, further biodistribution data were recorded after 24 h p.i. in AR42J tumor-bearing CD1-nu / nu mice with lutetium-177 (Table 4, Figure 7).

[0319] After 24 hours, there is still activity in the tumor with 10.32 ± 7.04%ID / g. The other organs show reduced accumulation values of 0.01 ± 0.01-2.14 ± 0.98%ID / g. [177Lu]Lu-

[0320] (SiFA)SeFe-rhTATE4 shows only an approx. 3-fold reduced dose in the tumor after 24 h compared to 1 h p.i.. This is consistent with the values obtained in the evaluation after 6 h p.i., and anyway once again illustrates the high therapeutic efficiency.

[0321] The T / B ratios of the lutetium-177-labeled compound [177Lu]Lu-(SiFA)SeFe-rhTATE4 are directly compared at the different times (1 , 6 and 24 h) in order to be able to discuss distribution over time (Table 5). All organs show a steadily increasing T / B-ratio over time, with the exception of muscle and bone. Here the 6 h values feature the highest T / B-ratios (muscle = 118.32 ± 24.68 %ID / g for 1 h p.i., 542.02 ± 396.48 %ID / g for 6 h p.i., 368.79 ± 247.24 %l D / g for 24 h p.i. and bone = 16.24 ± 1.60 %ID / g for 1 h p.i., 31.16 ± 15.29 %ID / g for 6 h p.i., 12.66 ± 5.43 %ID / g for 24 h p.i.). For these organs the radioactivity was below the calibration curve of the used detection device and therefore may be subjected to errors.

[0322] Table 4: Biodistribution of [19 / 18F][177 / natLu]Lu-(SiFA)SeFe-rhTATE4 in selected organs [%l D / g] at 1 h, 6h and 24 h p.i. in AR42J tumor-bearing female CD1-nu / nu mice. Bone + marrow 1.74 ± 0.45 1.56 1.97 ± 0.43* 0.77 ± 0.45* 1.31 ± 0.68

[0323] Bone 0.56 ± 0.29 0.89

[0324] Tumor 53.58 ± 5.51 1.96 32.15 ± 8.55 22.97 ± 12.04 10.32 ± 7.04

[0325] Table 5: T / B ratio of [18F][natLu]Lu-(SiFA)SeFe-rhTATE4 and [177Lu]Lu-(SiFA)SeFe-rhTATE4 in selected organs [%ID / g] at 1h p.i. in AR42J tumor-bearing female CD1-nu / nu mice.

[0326] CXCR4-targeted radiohybrid compound

[0327] To generate (SiFA)SeFe-rhCPCR4.1 (Figure 8) the rh-concept was applied to a CPCR4 analog containing the SiFA building block (SiFA)SeFe for18F-labeling and a DOTA chelator for177Lu-labeling. Previous unpublished studies have shown that the substitution of the 4-AMBA in Pentixafor with other aromatic systems is tolerated by CXCR4 in terms of affinity. Therefore (SiFA)SeFe was incorporated directly at CPCR4. Afterwards a linker sequence for affinity (-D-Ala-D-Arg-D-Dap-) and hydrophilicity (-D-Cit-D-Cit-D-Cit-) was introduced, followed by the chelator DOTA. • Synthesis of (SiFA)SeFe-rhCPCR4.1

[0328] Synthesis of CPCR4 binding motif

[0329] A 2-CTC-resin was loaded with Fmoc-Gly-OH (GS1). Afterwards an Fmoc-deprotection (GS2), the coupling of Fmoc-l-2-Nal-OH (GS3), Fmoc-l-Arg(Pbf)-OH (GS3), Fmoc-d-Orn(Boc)-OH (GS3), Ns-protection (GS4), / V-methylation (GS5), Ns-deprotection (GS6) and coupling of Fmoc-d-Tyr(tBu)-OH was performed. The peptide was then cleaved from the resin (GS7). A purification with a flash purification system (Biotage®, Upsalla, Sweden) was performed before the peptide was cyclised (GS8) and deprotected from acid labile protecting groups (GS9).

[0330] Synthesis of tripeptide 1 : Fmoc-d-Dap(Boc)-d-Arg(Pbf)-d-Ala-OH

[0331] A 2-CTC-resin was loaded with Fmoc-d-Ala-OH (GS1). Afterwards an Fmoc-deprotection (GS2), coupling of Fmoc-d-Arg(Pbf)-OH (GS3) and Fmoc-d-Dap(Boc)-OH (GS11) was performed. Here the final Fmoc-deprotection was not done. The peptide was cleaved from the resin (GS7).

[0332] Synthesis of tripeptide 2: Fmoc-d-Cit- d-Cit- d-Cit-OH

[0333] A 2-CTC-resin was loaded with Fmoc-d-Cit-OH (GS1). Afterwards an Fmoc-deprotection (GS2), coupling of two times Fmoc-d-Cit-OH (GS3) was performed. Here the final Fmoc- deprotection was not done. The peptide was cleaved from the resin (GS7).

[0334] To finally achieve the compound (SiFA)SeFe-rhCPCR4.1 a peptide coupling with Fmoc- (SiFA)SeFe as amino acid and CPCR4 as free amine was performed in solution (GS10). In details, tripeptide 1 and subsequently tripeptide 2 were coupled according to GS10. Afterwards DOTA(tBu)3 was coupled (GS11) and a final deprotection of the acid labile protection groups was performed (GS9).

[0335] GS1: Loading of the 2-CTC resin

[0336] The 2-chloro-tritylchlorid (2-CTC) resin (loading density: 1.6 mmol / g) was swollen for 30 min in 5 mL DMF. The resin was loaded with an Fmoc protected amino acid (AA) using Fmoc-AA-OH (1.5 eq.) and DIPEA ( / V, / V-Diisopropylethylamine) (4.5 eq.) in DMF (N,N- Dimethylformamide) in a 20 mL peptide syringe and the mixture was shaken at room temperature for 4 h. MeOH (1 mL / g resin) was added to the resin and shaken for 15 minutes. Afterwards, the resin was washed 5 times with DMF (5 mL) and 3 times with DCM (5 mL) and dried in a desiccator.

[0337] GS2: Fmoc deprotection

[0338] / V-terminal Fmoc-protected amino acids or peptides bound to the resin are deprotected by adding 20% piperidine in DMF (5 mL). The deprotection reagent is added twice (1 x5 min, 1 x15 min). The resin is then washed with DMF (6x with 5 mL each). GS3: Standard peptide coupling to the resin

[0339] Prior to coupling at the C-terminus of side-chain-protected Fmoc-AA-OH (1.5 eq.), preactivation is performed with TBTLI (1.5 eq.), HOAt (1.5 eq.), and DI PEA (4.5 eq.) in 5 mL DMF. After 10 min, the activated solution is added to the resin-bound peptide containing the free amine (2-CTC-AA-NH2) and shaken for 1.5 h at room temperature. The resin is then washed six times with DMF (5 mL) and Fmoc deprotected (GS2). For storage the resin was washed 3 times with DCM and dried in a desiccator.

[0340] GS4: Ns-protection p-Ns-CI (5.0 eq.) and collidine (10 eq.) are dissolved in NMP (10 mL / g resin). The solution is then added to the resin-bound free amine peptide and shaken for 15 min at r.t. After washing the resin 3 times with NMP and it is washed 3 times with dry THF.

[0341] GS5: Na-methylation

[0342] First triphenylphosphine (5.0 eq.) and MeOH (10 eq.) were dissolved in dry THF (10 mL / g resin) and added to the resin bound Ns-protected peptide and is shaken for 5 min at r.t. DIAD (5.0 eq.) in dry THF (10 ml / g resin) is added and is shaken for additional 30 min. Then the resin is washed 3 times with dry THF and 3 times with NMP.

[0343] GS6: Ns-de protect! on

[0344] The Ns-protected resin-bound peptide is incubated in DBU (5.0 eq.) in NMP (10 mL / g resin) for 5 min. Mercaptoethanol (10 eq.) in NMP (2 mL / g) resin is added. After 30 min the resin is washed 5 times with DMF.

[0345] GS7: Cleavage from the resin with retention of acid labile protective groups

[0346] The peptide bound to the resin is mixed with 5 mL of HFIP / DCM (v:v = 1 / 4) and stirred for 2x45 min at room temperature. The solution with the protected peptide is collected and then evaporated under a nitrogen stream. GS8: Cyclisation

[0347] The peptide is solved in 2 mL DMF and DIPEA (6.0 eq.). Then HATLI (3.0 eq.) in 0.5 mL DMF is added dropwise. The solution is stirred at r.t. for 60 min. The solvent is then removed under reduced pressure.

[0348] GS9: Deprotection of acid labile side chain protection groups

[0349] To the protected peptide 5 mL of a solution of TFA / TIPS / Water (v:v:v = 95 / 2.5 / 2.5) was added and stirred for 2 h before evaporating the solvent under a nitrogen stream. A subsequent HPLC-purification was performed.

[0350] GS10: Peptide coupling in solution

[0351] The Fmoc-protected AA (1 .5 eq.), TBTLI (1.5 eq.) and HOAt (1.5 eq.) were solved in 1 mL DMF and DI PEA (4.5 eq.) was added. After 10 min preactivation at r.t. the solution was added to the free amine peptide (1.0 eq.) in 1 mL DMF. The solution was stirred at r.t. for 2 h before adding 0.5 mL piperidin for Fmoc protection. It was stirred for another 15 min before removing the solvent under reduced pressure and subsequent HPLC-purification.

[0352] GS11: Coupling of Fmoc-D-Dap(Boc)-OH

[0353] Prior to coupling of Fmoc-D-Dap(Boc)-OH (1.5 eq.), preactivation is performed with TBTU (1.5 eq.), HOAt (1.5 eq.), and sym-collidine (6.0 eq.) in 5 mL DMF. After 10 min, the activated solution is added to the resin-bound peptide containing the free amine (2-CTC-AA-NH2) and shaken for 1.5 h at room temperature. The resin is then washed six times with DMF (5 mL) and Fmoc deprotected (GS2). For storage the resin was washed 3 times with DCM and dried in a desiccator.

[0354] GS12: Coupling of DOTA(tBu)3

[0355] DOTA(tBu)a (1 .5 eq.), TBTU (1 .5 eq.) and HOAt (1 .5 eq.) were solved in 1 mL DMF and DIPEA (4.5 eq.) was added. After 10 min preactivation at r.t. the solution was added to the free amine peptide (1.0 eq.) in 1 mL DMF. The solution was stirred at r.t. for 3 h before removing the solvent under reduced pressure. • Synthesis of cold metal complexes

[0356] Complexation withnatLu-luthetium

[0357] For the incorporation ofnatLu-luthetium, LuCh (20 mM in DMSO, 3.0 eq.) is added to a 2 mM solution of the compound in DMSO and diluted to 1 mM by addition of DMSO. The obtained solution is incubated at 90°C for 30 min.

[0358] RP-HPLC (10-60% MeCN / H2O with 0.1 % TFA, v / v, 15 min, A = 220 nm) for [natLu]Lu- (SiFA)SeFe-rhCPCR4.1: fR= 10.4 min.

[0359] MS (ESI positive): m / z calculated for [natLu]Lu-(SiFA)SeFe-rhCPCR4.1 : 2335.07, found: 1070.1 [M + 2H+]2+, 780.2 [M + 3H+]3+, 585.2 [M + 4H+]4+.

[0360] • Radiolabeling

[0361] Luthetium-177 labeling

[0362] For luthetium-177 labeling, the aq. [177Lu]LuCl3 (14 MBq) is added to 1 pL (1 nmol) of the ligand (1 mM stock in DMSO) and 10 pL of a NaOAc buffer (pH = 5.5). It was then heated to 90 °C for 15 min. After the reaction time 10 pL NaAsc (0.1 M) is added and the solution is filled to 100 pL with 0.04 M HOI. lodine-125 labeling 25I]I-FC131

[0363] For in vitro studies ( / Cso, n = 3), 50-150 pg of FC131 are dissolved in 20 pL of DMSO and 280 pL of TRIS buffer (25 mM TRIS-HCI, 0.4 mM NaCI, pH = 7.9) in a 1.5 mL Eppendorf reaction tube (Protein LowBind). The solution is transferred to another reaction tube (1.5 mL, Protein LowBind) coated with lodogen® (150 pg) and 5.00 pL of (10 - 20 MBq) [125l]Nal (74 TBq, 40 mM NaOH, HARTMANN ANALYTIC GmbH (Braunschweig, Germany)) is added. After 15 min at room temperature, the reaction is stopped by separation from the oxidant (lodogen®) and the crude product is purified by analytical RP-HPLC.10 vol% Na-ascorbate solution (100 mM in H2O, radiolysis quencher) is added to the resulting product solution. The radioactivity per mL of [125I]I-FC131 is determined by measuring aliquots in a / -counter. [125I]I-FC131 is stored at -4 °C and can be used for up to three weeks.

[0364] Radio-RP-HPLC (20-45% MeCN / H2O with 0.1 % TFA, v / v, 20 min): fR= 9.2 min. In vitro Evaluation

[0365] [nat / 177Lu]Lu-(SiFA)SeFe-rhCPCR4.1 was evaluated in in vitro experiments and compared with the clinical standards [nat / 68Ga]Ga-Pentixafor and [nat / 177Lu]Lu-Pentixather. The studies included determination of binding affinity to CXCR4 expressing Jurkat cells and lipophilicity (Table 6). Values for [nat / 68Ga]Ga-Pentixafor57and [nat / 177Lu]Lu-Pentixather58were taken from literature.

[0366] Cell culture

[0367] Before culturing hCXCR4 positive Jurkat human T-cell leukemia cells, all biochemicals used are heated to 37°C. Cells were split every 2-3 days depending on cell growth. For this a certain amount of the cells was discarded the cells were centrifuged (1300 rpm, 3 min), the excess media was discarded and the remaining cells were resuspended in fresh cultivation media (25 mL). Before cell assays the cells were counted with a Neubauer hemocytometer (Paul Marienfeld, Lauda-Kbnigshofen, Germany). The processed which requires sterile working were performed at a MSC-Advantage safety cabinet from Thermo Fisher Scientific Inc.

[0368] Binding affinity (IC50)

[0369] For determination of the binding affinity to CXCR4 Jurkat cells (400.000 cells in 200 pL HBSS + 1 % BSA) were incubated with the reference radio ligand [125I]I-FC131 (25 pL HBSS + 1 % BSA, lOO.OOOcpm) and 25 pL of the competitor at certain concentrations (10'4-10'1°M). For the control experiment 25 pL HBSS + 1 % BSA was added instead of the competitor. After the incubation time of 2 h at 4-9 °C it was centrifuged (1300 rpm, 3 min) and the supernatant was removed. The cells were washed twice by adding 200 pL HBSS + 1 % BSA, centrifugation (1300 rpm, 3 min) and combining the supernatants. For each concentration a triplicate with n = 3 is determined. The radioactivity in cell pellet and supernatant are determined by a / -counter and the corresponding / C50 values were calculated with GraphPad Prism (Graph Pad Software, San Diego, USA). For each ligand a triplicate with n = 3 is determined.

[0370] Lipophilicity (logDpH=7.4)

[0371] For the determination of the octanol-PBS partition coefficient (logDPH=7.4 values), 500 pL 1- octanol and 500 pL PBS (pH = 7.4) were added to a 1 .5 mL Protein LoBind® tube (n = 6). To each tube 0.5 MBq of the labeled component was added and vortexed for 3 min. After centrifugation (9.000 rpm, 5 min, room temperature), 100 pL of the octanol phase and 100 pL of the PBS phase were taken and quantified by / -counter. The experiment is repeated at least 6 times. Table 6: Summary of in v / fro evaluations of [nat / 177Lu]Lu-(SiFA)SeFe-rhCPCR4.1 , which include binding affinity ( / C50, n=3), and lipophilicity (logDPH7.4, n=6) compared to clinical standards.

[0372] Compound / C50[nM] logDph=74

[0373] [nat / 68Ga]Ga-PentiXafor5724.8 ± 2.5 -2.90 ± 0.08

[0374] [nat / 177Lu]Lu-PentiXather5814.6 ± 1.0 -1.76 ± 0.08 nat / 177Lu]Lu-(SiFA)SeFe-rhCPCR4.1 32.2 ± 6.3 -2.65 ± 0.07 The substitution of 4-AMBA with (SiFA)SeFe together with the optimized linker sequence -D-Ala-D-Arg-D-Dap leads to a binding affinity in the nanomolar range of [natLu]Lu- (SiFA)SeFe-rhCPCR4.1. This indicates that the modifications are well tolerated by CXCR4. Compared to [natLu]Lu-Pentixather there is a 2.2-fold decrease in affinity from 14.6 ± 1.0 nM to 32.2 ± 6.3 nM. In comparison to [natGa]Ga-Pentixafor there is only a 1.3-fold and decrease in affinity from 24.8 ± 2.5 nM to 32.2 ± 6.3 nM which could lead to a slightly lower but still promising tumor uptake in vivo.

[0375] The hydrophilicity of [177Lu]Lu-(SiFA)SeFe-rhCPCR4.1 is depicted by a logDPH=7.4 of -2.65 ± 0.07 which is in the ideal range for radio pharmaceuticals. The diagnostic reference [68Ga]Ga-Pentixafor has a slightly lower logDPH=7.4 of -2.90 ± 0.08 but is comparable to [177Lu]Lu-(SiFA)SeFe-rhCPCR4.1. The therapeutic reference [177Lu]Lu-Pentixather has a logOPH=7.4 of -1 76 ± 0.08, which is approximately one order of magnitude higher than [177Lu]Lu- (SiFA)SeFe-rhCPCR4.1. The hydrophilicity of [177Lu]Lu-(SiFA)SeFe-rhCPCR4.1 is in between the clinical standard ligands, which suggests a favorable renal excretion similar to [68Ga]Ga- Pentixafor.

[0376] GRPR-tarqeted radiohybrid compound

[0377] MJ959from the common GRPR-addressing ligand RM2 was chosen as the pharmacophore and synthesized with standard SPPS Fmoc-strategy. Afterwards the sequence -4-APipAc-D-Orn-D-Dap- was introduced because previous studies have shown, that at least 3 amino acids are necessary between MJ9 and a SiFA unit to keep the affinity to GRPR high. Afterwards, (SiFA)SeFe and the chelator DOTA were incorporated to apply the rh-concept to eventually achieve compound (SiFA)SeFe-rhGRPRI (Figure 9).

[0378] • Synthesis of ( SiFA ) SeFe-rhGRPR 1

[0379] A rink-amide resin was loaded with Fmoc-Leu-OH (GS1). After a Fmoc deprotection (GS2) Fmoc-(3S, 4S)Sta-OH (GS3), Fmoc-His(Trt)-OH (GS3), Fmoc-Gly-OH (GS3), Fmoc-Val-OH (GS3), Fmoc-Ala-OH (GS3), Fmoc-Trp(Boc)-OH (GS3), Fmoc-Gln(Trt)-OH (GS3), Fmoc-D- Phe-OH (GS3), Fmoc-4-APipAc-OH (GS3), Fmoc- D-Dap(Boc)-OH (GS4), Fmoc-D-Orn(Boc)- OH (GS3), Fmoc-4-APipAc-OH (GS3), Fmoc-(SiFA)SeFe-OH (GS3) and DOTA(tBu)3(GS5) were coupled and cleaved afterwards (GS6).

[0380] GS1: Loading of the rink-amide resin

[0381] The rink-amide resin (loading density: 0.8 mmol / g) was swollen for 30 min in 5 mL DMF. The resin was loaded with an Fmoc protected amino acid (AA) using Fmoc-AA-OH (1.5 eq.) and DIPEA ( / V, / V-Diisopropylethylamine) (4.5 eq.) in DMF ( / V, / V-Dimethylformamide) in a 20 mL peptide syringe and the mixture was shaken at room temperature for 4 h. Afterwards, the resin was washed 5 times with DMF (5 mL) and 3 times with DCM (5 mL) and dried in a desiccator.

[0382] GS2: Fmoc deprotection

[0383] / V-terminal Fmoc-protected amino acids or peptides bound to the resin are deprotected by adding 20% piperidine in DMF (5 mL). The deprotection reagent is added twice (1 x5 min, 1 x15 min). The resin is then washed with DMF (6x with 5 mL each).

[0384] GS3: Standard peptide coupling to the resin

[0385] Prior to coupling at the C-terminus of side-chain-protected Fmoc-AA-OH (1.5 eq.), preactivation is performed with TBTU (1.5 eq.), HOAt (1.5 eq.), and DI PEA (4.5 eq.) in 5 mL DMF. After 10 min, the activated solution is added to the resin-bound peptide containing the free amine (2-CTC-AA-NH2) and shaken for 1.5 h at room temperature. The resin is then washed six times with DMF (5 mL) and Fmoc deprotected (GS2). For storage the resin was washed 3 times with DCM and dried in a desiccator.

[0386] GS4: Coupling of Fmoc-D-Dap(Boc)-OH

[0387] Prior to coupling of Fmoc-D-Dap(Boc)-OH (1.5 eq.), preactivation is performed with TBTLI (1.5 eq.), HOAt (1.5 eq.), and sym-collidine (6.0 eq.) in 5 mL DMF. After 10 min, the activated solution is added to the resin-bound peptide containing the free amine (2-CTC-AA-NH2) and shaken for 1.5 h at room temperature. The resin is then washed six times with DMF (5 mL) and Fmoc deprotected (GS2). For storage the resin was washed 3 times with DCM and dried in a desiccator.

[0388] GS5: Coupling of DOTA(tBu)3

[0389] Prior to coupling of DOTA(tBu)3 (1.5 eq.), preactivation is performed with TBTU (1 .5 eq.), HOAt (1.5 eq.), and DIPEA (4.5 eq.) in 5 mL DMF. After 10 min, the activated solution is added to the resin-bound peptide containing the free amine (2-CTC-AA-NH2) and shaken for 3 h at room temperature. The resin is then washed six times with DMF (5 mL). For storage the resin was washed 3 times with DCM and dried in a desiccator.

[0390] GS6: Cleavage from resin and deprotection of acid labile side chain protection groups

[0391] To the swollen resin 5 mL of a solution of TFA / TIPS / Water (v:v:v = 95 / 2.5 / 2.5) was added and stirred for 1 h before the solution is renewed for another 1 h. The combined solutions are evaporated under a nitrogen stream. A subsequent HPLC-purification was performed.

[0392] • Synthesis of cold metal complexes

[0393] Complexation withnatLu-luthetium

[0394] For the incorporation ofnatLu-luthetium, LuCh (20 mM in DMSO, 3.0 eq.) is added to a 2 mM solution of the compound in DMSO and diluted to 1 mM by addition of DMSO. The obtained solution is incubated at 90°C for 30 min.

[0395] RP-HPLC (10-60% MeCN / H2O with 0.1 % TFA, v / v, 15 min, A = 220 nm) for [natLu]Lu- (SiFA)SeFe-rhGRPRI : fR= 10.8 min. • MS (ESI positive): m / z calculated for [natLu]Lu-(SiFA)SeFe-rhGRPR1 : 2444.19, found: 1224.0 [M + 2H+]2+, 816.7 [M + 3H+]3+, 612.8 [M + 4H+]4+. Radiolabelling

[0396] Luthetium-177 labeling

[0397] For luthetium-177 labeling, the aq. [177Lu]LuCh (14 MBq) is added to 1 pL (1 nmol) of the ligand (1 mM stock in DMSO) and 10 pL of a NaOAc buffer (pH = 5.5). It was then heated to 90 °C for 15 min. After the reaction time 10 pL NaAsc (0.1 M) is added and the solution is filled to 100 pL with 0.04 M HCI. lodine-125 labeling

[0398] [125l](3-l-tyr6)-MJ9

[0399] For in vitro studies ( / C50, n = 3), 50-150 pg of (tyr^-MJO are dissolved in 20 pL of Tracepur® H2O and 280 pL of TRIS buffer (25 mM TRIS-HCI, 0.4 mM NaCI, pH = 7.9) in a 1.5 mL Eppendorf reaction tube (Protein LowBind). The solution is transferred to another reaction tube (1.5 mL, Protein LowBind) coated with lodogen® (150 pg) and 5.00 pL of (10 - 20 MBq) [125l]Nal (74 TBq, 40 mM NaOH, HARTMANN ANALYTIC GmbH (Braunschweig, Germany)) is added. After 15 min at room temperature, the reaction is stopped by separation from the oxidant (lodogen®) and the crude product is purified by analytical RP-HPLC.The product is confirmed by coinjection of (3-l-tyr®)-MJ9. 10 vol% Na-ascorbate solution (100 mM in H2O, radiolysis quencher) is added to the resulting product solution. The radioactivity per mL of [125l](3-l-tyr6)- MJ9 is determined by measuring aliquots in a / -counter. [125l](3-l-tyr6)-MJ9 is stored at -4 °C and can be used for up to three weeks.

[0400] Radio-RP-HPLC (20-35% MeCN / H2O with 0.1 % TFA, v / v, 20 min): fR= 18.9 min.

[0401] In vitro Evaluation

[0402] [nat / 177Lu]Lu-(SiFA)SeFe-GRPR1 was evaluated in in vitro experiments and compared with literature reference [nat / 177Lu]Lu-RM2. The studies included determination of binding affinity to GRPR expressing PC-3 cells and lipophilicity (Table 7). Values for [nat / 177Lu]Lu-RM2 were taken from literature.60

[0403] Cell culture

[0404] Before culturing PC-3 cells, all biochemicals used are heated to 37°C. To control cell growth the cells were split every 3-4 days depending on cell growth. For this the media was removed and 8 ml trypsin / EDTA were added to the cell flask. The flasks were vigorously shaken for 2 min before being incubated in the incubator for 5 min. This was repeated 3 times. Afterwards the cells were centrifuged (1300 rpm, 3 min), the media was removed, fresh media was added and the pellet was resuspended. Excess cells were discarded depending on the amount of cells. The media was filled to 25 mL and the cells were put back in the incubator. Before cell assays the cells were counted with a Neubauer hemocytometer (Paul Marienfeld, Lauda- Kdnigshofen, Germany). The processed which requires sterile working were performed at a M SC- Ad vantage safety cabinet from Thermo Fisher Scientific Inc.

[0405] Binding affinity (IC50)

[0406] For determination of the binding affinity to GRPR PC-3 cells (150.000 cells per well per mL media) were incubated 24 ± 2 h prior to the experiment. The media was removed and the cells were washed once with 500 pL HBSS + 1% BSA before adding 200 pL HBSS + 1% BSA and let it equilibrate for 9 min. Afterwards 25 pL of the competitor in different concentrations (10'4-10'1° M in HBSS + 1 % BSA) and 25 pL of the reference ligand [125l](3- / -tyr6)MJ9 in HBSS + 1 % BSA (100.000 cpm per well) were added. For the control wells 25 pL of HBSS + 1% BSA was added instead of the competitor. The cells were incubated for2h at r.t. before removing the supernatant. One wash step of 300 pL of HBSS + 1% BSA was performed and it was combined with the previous supernatant. The remaining cells were lysated by adding 300 pL of 1 M NaOH and incubation for at least 15 min. The lysate was combined with the 300 pL of 1 M NaOH from the subsequent washing step. A triplicate (n = 3) was performed for each concentration step The radioactivity in the supernatant and the lysate was measured in a / -counter. The / C50 were calculated with GraphPad Prism (Graph Pad Software, San Diego, USA). For each ligand a triplicate with n = 3 is determined.

[0407] Lipophilicity (logDpH=7.4)

[0408] For the determination of the octanol-PBS partition coefficient (logDPH=7.4 values), 500 pL 1- octanol and 500 pL PBS (pH = 7.4) were added to a 1 .5 mL Protein LoBind® tube (n = 6). To each tube 0.5 MBq of the labeled component was added and vortexed for 3 min. After centrifugation (9.000 rpm, 5 min, r.t.), 100 pL of the octanol phase and 100 pL of the PBS phase were taken and quantified by / -counter. The experiment is repeated at least 6 times. Table 7: Summary of in vitro evaluations of [nat / 177Lu]Lu-(SiFA)SeFe-GRPR1, which include binding affinity ( / C50, n=3), and lipophilicity (logDPH7.4, n=6) compared to the standard [nat / 177Lu]Lu-RM2.

[0409] Compound / C50[nM] logDph=74 [nat / 177Lu]Lu-RM2603.45 ± 0.18 -2.51 ± 0.02 [nat / 177Lu]Lu-(SiFA)SeFe-rhGRPR1 2.57 ± 0.07 -1.60 ± 0.04 [natLu]Lu-(SiFA)SeFe-rhGRPR1 has an increased affinity towards GRPR compared to the standard [natLu]Lu-RM2 with an / C50 of 2.57 ± 0.07 nM compared to 3.45 ± 0.18 nM.

[0410] The lipophilicity of [177Lu]Lu-(SiFA)SeFe-rhGRPR1 is considerably higher than the one of [177Lu]Lu-RM2; however, the logDPH=7.4 of -1.60 ± 0.04 is still in a good range for radio pharmaceuticals. [nat / 177Lu]Lu-(SiFA)SeFe-rhGRPR1 was developed as a proof-of-concept ligand to show the influence of (SiFA)SeFe on a MJ9 based radio hybrid ligand. MJ9 is known to be instable in vivo and can be stabilized by exchanging the Trp9with a A / Me-Trp.61Also the sequence -4-APipAc-D-Orn-D-Dap- was shown to remarkably increase kidney uptake.

[0411] Brief Description of the Figures:

[0412] Figure 1 shows a schematic representation of the SiFA building blocks. Current SiFAs: (SiFA)BA38, (SiFA)A37and SiFAIin43building blocks (A). New building block: (SiFA)SeFe (B).

[0413] Figure 2 shows the chemical structure of the radio-hybrid compound (SiFA)SeFe-rhTATE4 in a version where a Lu3+cation is complexed by the chelating group.

[0414] Figure 3 shows the main steps of the synthesis of Fmoc-(SiFA)SeFe.

[0415] Figure 4 shows the biodistribution data of [18F][natLu]Lu-(SiFA)SeFe-rhTATE4 in selected organs after 1 h post injection (p.i.) in AR42J tumor-bearing CD1-nu / nu mice (300 pmol each). Data are expressed as %l D / g, mean ± SD (n = 3).

[0416] Figure 5 shows the biodistribution of [18F][natLu]Lu-(SiFA)SeFe-rhTATE4 (black) and competition study (grey) (47 pmol, + 40 nmol [natGa]DOTA-TATE) at 1 h p.i. in AR42J tumorbearing female CD1-nu / nu mice.

[0417] Figure 6 shows the biodistribution data of [18F][natLu]Lu-(SiFA)SeFe-rhTATE4 (black) in comparison to [177Lu]Lu-(SiFA)SeFe-rhTATE4 (grey) in selected organs after 1 h post injection (p.i.) in AR42J tumor-bearing CD1-nu / nu mice (300 pmol each). Data are expressed as %l D / g, mean ± SD (n = 3 and n = 6, respectively). *Data falling below the detection limit of the instrument and out of linear regression).

[0418] Figure 7 shows the biodistribution data of [177Lu]Lu-(SiFA)SeFe-rhTATE4 in selected organs after 24 h post injection (p.i.) in AR42J tumor-bearing CD1-nu / nu mice (300 pmol each). Data are expressed as %l D / g, mean ± SD (n = 5).

[0419] Figure 8 shows the chemical structure of the radio-hybrid compound (SiFA)SeFe-rhCPCR4.1 in a version where a Lu3+cation is complexed by the chelating group.

[0420] Figure 9 shows the chemical structure of the radio-hybrid compound (SiFA)SeFe-rhGRPRI in a version where a Lu3+cation is complexed by the chelating group. References

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Claims

Claims1. A compound of formula (IA) or formula (IB) or a salt thereof:whereinRTrepresents a targeting moiety which targets a structure of therapeutic and / or diagnostic interest;L1Aand L1Beach independently represents a divalent linking group, or is absent;L2Aand L2Beach independently represents a divalent linking group, or is absent;RCHrepresents (i) a chelating group or (ii) a chelate group wherein the chelating group comprises a complexed radioactive or non-radioactive metal cation, and the fluorine atom F attached to the silicon atom Si in formula (IA) and in formula (IB) is independently selected from radioactive [18F]fluorine and non-radioactive [19F]fluorine.

2. The compound or salt in accordance with claim 1 , wherein RCHrepresents (i) a chelating group which is provided by a chelating agent selected from the group consisting of DOTA, DOTAGA, DOTAM, D03AM, NOTA and NODAGA or (ii) a chelate group wherein any one of these chelating groups comprises a complexed radioactive or non-radioactive metal cation.

3. The compound or salt in accordance with claim 1 or 2, wherein the complexed metal cation is selected fromnatGa3+,68Ga3+,natLu3+,177Lu3+,90Y3+andnatY3+, more preferably fromnatGa3+,68Ga3+,natLu3+, and177Lu3+.

4. The compound or salt in accordance with any one of claims 1 to 3, wherein RCHrepresents a chelating group of formula (CH-1) or a chelate group of any of formulae (CH-2) or (CH-3):wherein the waved line marks a bond which attaches the group to the remainder of the compound, the complexed Lu3+cation in formula (CH-2) is selected from a cation of non-radioactivenatLu and a cation of radioactive177Lu, and the complexed Ga3+cation is selected from a cation of non-radioactivenatGa and a cation of radioactive68Ga.

5. The compound or salt in accordance with any one of claims 1 to 4, wherein the targeting moiety RTrepresents a peptide moiety.

6. The compound or salt in accordance with claim 5, wherein the peptide moiety comprises 3 to 20 amino acid units.

7. The compound or salt in accordance with any one of claims 1 to 6, wherein the targeting moiety RTrepresents a targeting moiety which targets a structure selected from the group consisting of a somatostatin receptor, a gastrin releasing peptide receptor , a C-X-C chemokine receptor type 4, a glucagon-like peptide-1 receptor, a cholecystokinin B receptor, prostate specific membrane antigen, fibroblast activation protein alpha, an integrin, and neurokinin-1 , or is a blood brain barrier crossing peptide.

8. The compound or salt in accordance with claim 7, wherein the targeting moiety RTis a targeting moiety RTATEhaving the following structure (TA-1):wherein the waved line marks a bond which attaches the moiety to the remainder of the compound.

9. The compound or salt in accordance with claim 7, wherein the targeting moiety RTis a targeting moiety RCPCR4which targets a C-X-C chemokine receptor type 4 (CXCR4) and has the following structure (TA-2):whereinRB1is selected from hydrogen (-H) and iodine (-I), and is preferably H, RB2is an alkanediyl group, preferably propanediyl, and most preferably -CH2-CH2-CH2-, and wherein the waved line marks a bond which attaches the moiety to the remainder of the compound.

10. The compound or salt in accordance with claim 7, wherein the targeting moiety RTis a targeting moiety RGRPRwhich targets a gastrin releasing peptide receptor (GRPR) and has the following structure (TA-3):(TA-3) wherein the waved line marks a bond which attaches the moiety to the remainder of the compound, and wherein:RB3is selected from -CH2-CH2-C(O)-NH2 and -CH2-CH2-CH2OH, and is preferably -CH2-CH2- C(O)-NH2, RB4is selected from -H and -CH3, and is preferably -CH3, and XBis selected from NH and S, and is preferably NH.

11. The compound or salt in accordance with any one of claims 1 to 10, wherein each of L1Aand L1Bis selected from a divalent amino acid moiety and a divalent oligopeptide moiety, or is absent.

12. The compound or salt in accordance with claim 11 , wherein the divalent oligopeptide moiety comprises 2 to 5, preferably 2 or 3 amino acid units.

13. The compound or salt in accordance with any one of claims 1 to 12, wherein each ofL2Aand L2Bis selected from a divalent amino acid moiety and a divalent oligopeptide moiety, or is absent.

14. The compound or salt in accordance with claim 13, wherein the divalent oligopeptide moiety comprises 2 to 7, preferably 2 to 6 amino acid units.

15. A pharmaceutical composition comprising or consisting of one or more compounds or salts in accordance with any one of claims 1 to 14.

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