radiopharmaceutical

Abstract

P360293WO 44 Abstract Provided is a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or hydrate thereof which can be used as a radiopharmaceutical agent for the imaging and / or treatment of diseases. Also provided are conjugates of the compound of formula (I) with radionuclides and uses of the conjugates and compositions comprising the conjugates for 5 the imaging and / or treatment of diseases. (I) [Figure 1]

Description

[0001] Radiopharmaceutical Field of the invention The present invention relates to a compound and a radiopharmaceutical agent formed therefrom that can be used for the imaging and / or treatment of diseases such as cancer. Background to the invention The global increases in cancer diagnoses and deaths have led to a huge demand on the development of cancer research for diagnostic and therapeutic applications. Despite the significant improvement in the prognosis for patients over the past decades, the emergence of treatment resistance after the standard of care such as radiotherapy and chemotherapy are frequently observed, hence the need for new selective, mechanism-based therapeutics to tackle this life-threatening disease. Personalized medicines, such as molecular radionuclide therapy (MRT), can provide patients with more effective treatments based on their genetic make-up and clinical needs, in which the current conventional chemotherapy and radiotherapy cannot achieve. MRT is one of the modern nuclear medicine methods that utilizes targeted radiopharmaceuticals to deliver ionizing radiation selectively to tumor sites to kill cancer cells. The same molecular scaffold, when replaced with a diagnosis radionuclide also allows non-invasive visualization of the lesions in whole body via PET (positron emission tomography) or SPECT (single- photon emission computed tomography) imaging. Targeting poly (ADP-ribose)polymerase (PARP), a family of DNA damage repair (DDR) genes which play an important part in regulating of various DDR pathways to help with DNA damage repair, is a fast-expanding field for cancer therapy. Aberrant expressions of PARP-1 has been found in many cancers including breast, pancreatic and prostate cancers, hence targeting PARP becomes a potential therapeutic strategy for cancer subtype carrying DDR gene mutations or high PARP expressions. PARP inhibitors (PARPi) are widely used in clinical practice for primarily BRCA-mutated cancers as single agent therapy or in combination with radiotherapy or targeted therapies to improve treatment efficacy. Unlike the conventional radiotherapy, the use of PARP-targeting radiotherapeutics offers a novel cancer therapeutic method to disrupt DDR pathway by creating DNA damages selectively in cancer cells to induce cell death, thereby minimizing the potential radiotoxicity incurred onto the nearby healthy tissues. In recent years, several radiolabeled-PARP inhibitors (r-PARPi) have been developed and demonstrated the potential of PARP imaging and MRT in preclinical studies, primarily involving radiohalogen such as18F-,123I,77Br, or211At-labeled PARPi radiopharmaceuticals. However, these compounds possess high lipophilic properties where they are primarily excreted via liver and bile, resulting in a high radioactivity accumulation in the abdominal region. Such physiological distribution may limit the imaging capacity towards gastrointestinal cancers or detection of small and metastatic lesions around that region, a common issue observed in the case of metastatic pancreatic and ovarian cancers. In addition, high physiological expressions of PARP-1 in liver, spleen, lymph node and bone marrow coupled with slow radioactivity clearance in these organs can increase the risk of radiation toxicity to these healthy organs. This significantly limits their radiopharmaceutical therapeutic applications. Hence there is an unmet need to improve the pharmacokinetics of rPARPi to allow whole- body imaging (including abdominal imaging) and MRT applications. The current invention has been devised with these issues in mind. Summary of the invention According to a first aspect of the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or hydrate thereof: wherein: Z is a PARP inhibitor m is an integer from 0 to 6; n is an integer from 1 to 4; L is a bond, -O-, -S-, or -NH-; and R1is H, OH, C(O)OH, C(O)NH2or C(O)NR3OH; each R2is independently selected from OH and NR3OH; and each R3is independently selected from H, CH3and CH2CH3; According to a second aspect of the invention there is provided a conjugate comprising the compound of the first aspect complexed with a radionuclide. The radionuclide may be selected from177Lu,68Ga,64Cu,67Cu,67Ga,111In, Al-18F,89Zr,255Ac,86Y,90Y,186Re,188Re,44Sc,152Tb,161Tb,169Er,165Er,47Sc,155Tb,175Yb and99mTc. According to a third aspect of the invention there is provided a composition comprising the compound of the first aspect, or the conjugate of the second aspect, and a pharmaceutically acceptable excipient. According to a fourth aspect of the invention there is provided the conjugate of the second aspect, or the composition of the third aspect, for use as a medicament. According to a fifth aspect of the invention there is provided the conjugate of the second aspect, or the composition of the third aspect, for use as a diagnostic or imaging agent. According to a sixth aspect of the invention there is provided the conjugate of the second aspect, or the composition of the third aspect, for use in the treatment of cancer. According to a seventh aspect of the invention there is provided a method of detecting cancer in a subject, said method comprising imaging a subject who has received the conjugate of the second aspect, or the composition of the third aspect. According to a eight aspect of the invention there is provided a kit comprising a compound according to the first aspect and a radionuclide. According to a ninth aspect of the invention there is provided a method of treating cancer in a subject comprising administering to the subject the conjugate of the second aspect, or the composition of the third aspect. According to a tenth aspect of the invention there is provided the conjugate of the second aspect, or the composition of the third aspect, for use in the manufacture of a medicament for the treatment of cancer. Brief description of figures Embodiments of the invention will now be described by way of example with reference to the figures in which: Figure 1 shows the binding affinity of a compound according to the invention (KK02) to PARP-1 as determined by colorimetric assay kit; Figure 2 shows the radioactivity (grey) and UV absorbance (black) HPLC chromatograms from co-injection of68Ga-KK02 andnGa-KK02; Figure 3 shows radiochemical yield and molar activity calculations for68Ga-KK02; Figure 4 shows stability measurements (up to 3 h) of68Ga-KK02 in human serum; Figure 5 shows a radio-TLC spectrum of177Lu-KK02; Figure 6 shows stability measurements (up to 7 days) of177Lu-KK02 in PBS, saline and mouse serum; Figures 7A shows a representative western blot probing for PARP-1 expression levels in a panel of breast cancer cell lines; Figure 7B shows quantification of band intensity of the western blot of Figure 7A, presented as a percentage of relative densitometry normalized to the ^-actin; Figure 8 shows the uptake of68Ga-KK02 in human triple negative breast cancer (TNBC) cells (MDA-MB-231 and MDA-MB-436) 30 min after addition of the radiotracer; Figure 9 shows blocking of68Ga-KK02 uptake in MDA-MB-231 cells with Olaparib; Figure 10 shows blocking of68Ga-KK02 uptake in MDA-MB-436 cells with one of a panel of PARP inhibitors (100 ^M); Figure 11 shows a time dependency uptake assay of177Lu-KK02 in TNBC cells; Figure 12 shows blocking of177Lu-KK02 uptake in TNBC cells with one of different clinically used PARP inhibitors (100 ^M). Data presented as mean ± SD. Asterisks indicate levels of significance: *, P < 0.05, **, P < 0.01; ***, P < 0.001; and ****, P < 0.0001; Figure 13 shows the uptake of177Lu-KK02 in human prostate (22Rv1 and LNCaP) and pancreatic (AsPC1 and PSN1) cancer cells 30 min after addition of the radiotracer. A higher177Lu-KK02 uptake is positively correlated with increased expression of PARP-1 mRNA in these cells (i.e. High PARP-expressing: 22Rv1, moderate PARP-expressing: LNCaP and PSN1, low PARP-expressing: AsPC1) based on PARP-1 mRNA data from publicly available database; Figure 14 shows PARP-1, PARP-2, and PARP-3 mRNA expression levels across different cancer cells of investigation derived publicly available database. A higher177Lu-KK02 uptake is positively correlated with a higher PARP-1 mRNA expression in these cancer cells.; Figure 15 shows a time dependency uptake assay of177Lu-KK02 in prostate (22Rv1 and LNCaP) and pancreatic (AsPC1 and PSN1) cancer cells; Figure 16 shows blocking assays of177Lu-KK02 in different cancer cells with a panel of clinically used PARP inhibitors (100 ^M); Figure 17 shows the retention (at 1 h) of177Lu-KK02 in 22Rv1 and PSN1 cells; Figure 18 shows AsPC1, PSN1 and 22Rv1 cells treated with177Lu-KK02 (0–100 kBq, Am = 22–49.8 MBq / nmol) analyzed by flow cytometry for total cell death; Figure 19 shows the percentage accumulation of ^H2AX in AsPC1 and PSN1 cells with and without exposure to177Lu-KK02 (0–100 kBq, Am = 22–49.8 MBq / nmol). Data presented as mean ± SD. Asterisks indicate levels of significance: *, P < 0.05, **, P < 0.01; ***, P < 0.001; and ****, P < 0.0001; Figure 20 shows the clonogenic survival of MDA-MB-231 and MDA-MB-436 cells after 3 h exposure to177Lu-KK02 (0.01–100 kBq, Am= 31.8 MBq / nmol, total amount of complex: 0.31–3100 fmol). Data presented as mean ± SD. Asterisks indicate levels of significance: *, P < 0.05; Figure 21 shows representative dynamic PET images immediately after intravenous injection of68Ga-KK02 (11.1–18.5 MBq, Am= 3.3–4.9 MBq / nmol) in healthy nude mice. Middle of time frames is indicated in minutes; Figure 22 shows ex vivo biodistribution studies in selected tissues of healthy nude mice at various timepoints (5, 15, 30, 60, 120, 180 mins, n=4 per timepoint) after intravenous administration of68Ga-KK02 (1.9–7.4 MBq, Am= 3.3–4.9 MBq / nmol); Figure 23 shows representative PET / MR images at 1 h after intravenous administration of68Ga-KK02 (5.6–9.3 MBq, Am= 3.3–4.9 MBq / nmol) in MDA-MB-436 mice. An excess of olaparib (0.5 mg) was given prior to68Ga-KK02 injection to demonstrate in vivo specificity. Tumors are circled in white; Figure 24 shows representative PET / MR images at 1 h after intravenous injection of68Ga- KK02 (5.6–9.3 MBq, Am= 3.3–4.9 MBq / nmol) in MDA-MB-231 mice. An excess of olaparib (0.5 mg) was given prior to68Ga-KK02 injection to demonstrate in vivo specificity. Tumors are circled; Figure 25 shows the ex vivo biodistribution in selected tissues of MDA-MB-436 tumor- bearing mice at 1 h after intravenous injection of68Ga-KK02 (5.6–9.3 MBq, Am = 3.3–4.9 MBq / nmol), with or without an excess of olaparib or talazoparib (0.5 mg, n=3 per group); Figure 26 shows biodistribution studies in selected tissues of healthy FVB mice at various timepoints (1, 2, 24 and 48 h, n=4 per timepoint) after intravenous administration of177Lu- KK02 (2.1–4.6 MBq, Am = 22–49.8 MBq / nmol); Figure 27 shows representative SPECT / CT images (Right) and PET / MRI images (Left) at 1 h after intraveneous administration of177Lu-KK02 (8–11.2 MBq, Am = 22–49.8 MBq / nmol) or68Ga-KK02 (1.85–7.4 MBq, Am = 3.3-4.9 MBq / nmol), respectively, in MDA-MB-436 tumor- bearing mice. Tumors are circled; Figure 28 shows the ex vivo biodistribution in selected tissues of MDA-MB-436 tumor- bearing mice at 1 h after intravenous injection of177Lu-KK02 (8-11.2 MBq, Am = 45.6 MBq / nmol), with or without an excess of olaparib or talazoparib (0.5 mg, n=3 per group); Figure 29 shows the autoradiography of MDA-MB-436 tumor sections harvested at 1 h after intravenous injection of either68Ga-KK02 (Left, 5.6–9.3 MBq, Am = 3.3–4.9 MBq / nmol) or177Lu-KK02 (Right, 8–11.2 MBq, Am= 22–49.8 MBq / nmol), with or without an excess of olaparib (0.5 mg); Figure 30 shows tumor growth after single administration of177Lu-KK02 (n=3 per group, 60 MBq, Am= 22–49.8 MBq / nmol) or vehicle control (n=5 per group). Asterisks indicate levels of significance: *, P < 0.05; and Figure 31 shows the expression of total myeloid cells in bone marrow collected from mice receiving177Lu-KK02 or vehicle control. A first aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or hydrate thereof: wherein: Z is a PARP inhibitor; m is an integer from 0 to 6; n is an integer from 1 to 4; L is a bond, -O-, -S-, or -NH-; R1 is H, OH, C(O)OH, C(O)NH2 or C(O)NR3OH; each R2 is independently selected from OH and NR3OH; and each R3 is independently selected from H, CH3 and CH2CH3. It may be that n is 1, 2, 3 or 4. In some embodiments, n is 1 or 2. In some embodiments, n is 2. In some embodiments, R1 is H or C(O)OH. In some embodiments, R1 is C(O)OH. In some embodiments, L is a bond or -O-. In some embodiments, L is a bond. In some embodiments, each R2is OH. It may be that m is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, m is 0, 1 or 2. In some embodiments, m is 0. In some embodiments each R3is H. In some embodiments each R3is CH3. In some embodiments each R3is CH2CH3. Z is a poly ADP ribose polymerase (PARP) inhibitor. Suitable PARP inhibitors will be known to those skilled in the art. The PARP inhibitor may be, or it may be derived from, Olaparib, Rucaparib, Veliparib, Niraparib, Talazoparib, Pamiparib, CEP-9722, EZ449, E7016, AZD5305, or MK-4827. By “derived from”, it will be understood that an atom, functional group or moiety of the PARP inhibitor has been altered (e.g. removed or replaced) in order to form a bond with the rest of the compound of the invention, but that the PARP inhibitory effects are retained. In some embodiments, the PARP inhibitor (Z) is, or is derived from, Olaparib. In some embodiments, Z is: In some embodiments, the compound of formula (I) has the structure of formula (II): In some embodiments of formula (II): (A) L is a bond, m is 0, R1 is C(O)OH, each R2 is OH and n is an integer from 1 to 4; (Bi) L is a bond, m is 0, R1 is C(O)OH, each R2 is NR3OH, R3 is H, and n is an integer from 1 to 4; (Bii) L is a bond, m is 0, R1 is C(O)OH, each R2 is NR3OH, R3 is CH3 and n is an integer from 1 to 4; (Biii) L is a bond, m is 0, R1 is C(O)OH, each R2 is NR3OH, R3 is CH2CH3 and n is an integer from 1 to 4; (C) L is a bond, m is 0, R1 is H, each R2 is OH, and n is an integer from 1 to 4; (Di) L is a bond, m is 0, R1 is H, each R2 is NR3OH, R3 is H and n is an integer from 1 to 4; (Dii) L is a bond, m is 0, R1 is H, each R2 is NR3OH, R3 is CH3 and n is an integer from 1 to 4; (Diii) L is a bond, m is 0, R1 is H, each R2 is NR3OH, R3 is CH2CH3 and n is an integer from 1 to 4; (E) L is a bond, m is 0, R1 is OH, each R2 is OH, and n is an integer from 1 to 4; (Fi) L is a bond, m is 0, R1 is OH, each R2 is NR3OH, R3 is H and n is an integer from 1 to 4; (Fii) L is a bond, m is 0, R1 is OH, each R2 is NR3OH, R3 is CH3 and n is an integer from 1 to 4; (Fiii) L is a bond, m is 0, R1 is OH, each R2 is NR3OH, R3 is CH2CH3 and n is an integer from 1 to 4; (Gi) L is a bond, m is 0, R1 is C(O)NR3OH, each R2 is OH, R3 is H and n is an integer from 1 to 4; (Gii) L is a bond, m is 0, R1is C(O)NR3OH, each R2is OH, R3is CH3and n is an integer from 1 to 4; (Giii) L is a bond, m is 0, R1is C(O)NR3OH, each R2is OH, R3is CH2CH3and n is an integer from 1 to 4; (Hi) L is a bond, m is 0, R1is C(O)NR3OH, each R2is N(CH3)OH, R3is H and n is an integer from 1 to 4; (Hii) L is a bond, m is 0, R1is C(O)NR3OH, each R2is N(CH3)OH, R3is CH3and n is an integer from 1 to 4; (Hiii) L is a bond, m is 0, R1is C(O)NR3OH, each R2is N(CH3)OH, R3is CH2CH3and n is an integer from 1 to 4; (Ii) L is a bond, m is 0, R1is C(O)NR3OH, each R2is NHOH, R3is H and n is an integer from 1 to 4; (Iii) L is a bond, m is 0, R1is C(O)NR3OH, each R2is NHOH, R3is CH3and n is an integer from 1 to 4; (Iiii) L is a bond, m is 0, R1is C(O)NR3OH, each R2is NHOH, R3is CH2CH3and n is an integer from 1 to 4; (Ji) L is a bond, m is 0, R1is C(O)NR3OH, each R2is N(CH2CH3)OH, R3is H and n is an integer from 1 to 4; (Jii) L is a bond, m is 0, R1is C(O)NR3OH, each R2is N(CH2CH3)OH, R3is CH3and n is an integer from 1 to 4; (Jiii) L is a bond, m is 0, R1is C(O)NR3OH, each R2is N(CH2CH3)OH, R3is CH2CH3and n is an integer from 1 to 4; (K) L is a bond, m is 0, R1 is C(O)NH2, each R2 is OH, n is an integer from 1 to 4; (Li) L is a bond, m is 0, R1 is C(O)NH2, each R2 is NHOH, n is an integer from 1 to 4 (Lii) L is a bond, m is 0, R1 is C(O)NH2, each R2 is N(CH3)OH, n is an integer from 1 to 4. (Liii) L is a bond, m is 0, R1 is C(O)NH2, each R2 is N(CH2CH3)OH, n is an integer from 1 to 4 In any of embodiments (A) to (Liii) above, n may be 1, 2, 3 or 4. In some embodiments n is 1. In some embodiments, n is 2. In some embodiments, the compound of formula (I) has the structure: wherein Z is as defined herein. In some embodiments, the compound of formula (I) has the structure:

[0002] wherein Z is as defined herein. In some embodiments, the compound of formula (I) has the structure: In some embodiments, the compound of formula (I) has the structure of formula (III): In some embodiments of formula (III): (M) R1is H, each R2is OH, and m is an integer from 1 to 6; (Ni) R1is H, each R2is NHOH, and m is an integer from 1 to 6; (Nii) R1is H, each R2is N(CH3)OH, and m is an integer from 1 to 6; (Niii) R1is H, each R2is N(CH2CH3)OH, and m is an integer from 1 to 6; (O) R1is OH, each R2is OH, and m is an integer from 1 to 6. (Pi) R1is OH, each R2is NHOH, and m is an integer from 1 to 6; (Pii) R1is OH, each R2is N(CH3)OH, and m is an integer from 1 to 6; (Piii) R1is OH, each R2is N(CH2CH3)OH, and m is an integer from 1 to 6; (Q) R1is C(O)OH, each R2is OH, and m is an integer from 1 to 6; (Ri) R1is C(O)OH, each R2is NHOH, and m is an integer from 1 to 6; (Rii) R1is C(O)OH, each R2is N(CH3)OH, and m is an integer from 1 to 6; (Riii) R1is C(O)OH, each R2is N(CH2CH3)OH, and m is an integer from 1 to 6; (S) R1is C(O)NH2, each R2is OH, and m is an integer from 1 to 6; (Ti) R1is C(O)NH2, each R2is NHOH, and m is an integer from 1 to 6; (Tii) R1is C(O)NH2, each R2is N(CH3)OH, and m is an integer from 1 to 6; (Tiii) R1is C(O)NH2, each R2is N(CH2CH3)OH, and m is an integer from 1 to 6. (Ui) R1is C(O)NR3OH, each R2is OH, R3is H and m is an integer from 1 to 6; (Uii) R1is C(O)NR3OH, each R2is OH, R3is CH3and m is an integer from 1 to 6; (Uiii) R1 is C(O)NR3OH, each R2 is OH, R3 is CH2CH3 and m is an integer from 1 to 6; (Vi) R1 is C(O)NR3OH, each R2 is NHOH, R3 is H and m is an integer from 1 to 6; (Vii) R1 is C(O)NR3OH, each R2 is NHOH, R3 is CH3 and m is an integer from 1 to 6; (Viii) R1 is C(O)NR3OH, each R2 is NHOH, R3 is CH2CH3 and m is an integer from 1 to 6; (Wi) R1 is C(O)NR3OH, each R2 is N(CH3)OH, R3 is H and m is an integer from 1 to 6; (Wii) R1 is C(O)NR3OH, each R2 is N(CH3)OH, R3 is CH3 and m is an integer from 1 to 6; (Wiii) R1 is C(O)NR3OH, each R2 is N(CH3)OH, R3 is CH2CH3 and m is an integer from 1 to 6; (Xi) R1 is C(O)NR3OH, each R2 is N(CH2CH3)OH, R3 is H and m is an integer from 1 to 6; (Xii) R1 is C(O)NR3OH, each R2 is N(CH2CH3)OH, R3 is CH3 and m is an integer from 1 to 6; (Xiii) R1 is C(O)NR3OH, each R2 is N(CH2CH3)OH, R3 is CH2CH3 and m is an integer from 1 to 6. In any of embodiments (M) to (Xiii) above, m is selected from 1, 2, 3, 4, 5 and 6. In some embodiments m is 1. In some embodiments m is 2. In some embodiments, the compound of formula (I) has the structure (referred to herein as “KK02”):

[0003] In some embodiments, the compound of formula (I) has the structure: wherein each R3is independently selected from H, CH3and CH2CH3. In some embodiments, each R3is H. In some embodiments each R3is CH3. In some embodiments, each R3is CH2CH3. In some embodiments, the compound of formula (I) has the structure: . In some embodiments, the compound of formula (I) has the structure: In some embodiments, the compound of formula (I) has the structure: The invention also provides an intermediate having the structure of formula (IV): (formula IV), wherein: L is a bond, -O-, -S-, or -NH-; and m is an integer from 0 to 6. In some embodiments of formula (IV), L is a bond or -O-. In some embodiments of formula (IV), m is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, L is -O- and m is an integer of 1 to 6. In some embodiments the intermediate of formula (IV) has the structure: In some embodiments the intermediate of formula (IV) has the structure: A second aspect of the invention provides a conjugate comprising the compound of the first aspect, wherein the compound is complexed with a radionuclide. Without being bound by theory, it is thought that the carbonyl group between L and n in formula (I) further increases the stability of the resulting conjugate. Surprisingly, a conjugate comprising the compound KK02 and177Lu (referred to herein as “177Lu-KK02”) showed remarkable stability in mouse serum. This was demonstrated by incubating177Lu-KK02 in mouse serum for 7 days. On the 7thday it was observed that >90% of177Lu remained conjugated to KK02, with a small amount of the ‘free’177Lu having been displaced. Such stability has not been observed in other similar radiotracers. Thus, in some embodiments, at least 90% of the radionuclide remains conjugated (i.e. at least 90% of the radionuclide is bound by the chelating moiety) following incubation of the compound in serum (e.g. mouse or human serum) for at least 5 days, at least 6 days or at least 7 days. The stability of the conjugate in serum can be determined using the methods described herein. Advantageously the chelating moiety of formula (I) is able to form complexes with a range of metals, thus providing the opportunity to chelate radionuclides for either therapeutic or diagnostic purposes. In some embodiments the radionuclide is selected to provide a conjugate having a therapeutic effect. As used herein, the term “radionuclide,” refers to an atom capable of undergoing radioactive decay. The terms “radioactive nuclide”, “radioisotope”, or “radioactive isotope” may also be used to describe a radionuclide. Radionuclides may be used as detection and / or therapeutic agents, as described herein. In some embodiments the radionuclide is selected to provide a conjugate which is suitable for diagnostic use. In some embodiments, the radionuclide is selected from177Lu,68Ga,64Cu,67Cu,67Ga,111In, Al-18F,89Zr,255Ac,86Y,90Y,186Re,188Re,44Sc,152Tb,161Tb,169Er,165Er,47Sc,155Tb,175Yb and99mTc. In some embodiments, the radionuclide is177Lu. In some embodiments, the radionuclide is68Ga. In another aspect, the invention provides a method of making a conjugate (e.g., any of the conjugates described herein). The method comprises adding a radionuclide (e.g.,177Lu or68Ga) to a solution comprising a compound as described herein at a temperature of at least 70° C (e.g., 80-100° C). The invention further provides a composition comprising a compound or a conjugate as described herein, and a pharmaceutically acceptable excipient. A “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Suitable pharmaceutically acceptable excipients will be known to those skilled in the art. The excipient may comprise one or more of: stabilisers, binders, dyes, emulsifiers, preservatives, radioprotectants, radiostabilizers, suspending or dispersing agents, ion exchangers, anti-oxidants, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, a buffer such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol. Exemplary excipients include, but are not limited to: ascorbic acid, histidine, phosphate buffer, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. The term “pharmaceutically acceptable salt", as used herein, refers to salts derived from a variety of organic and inorganic counter ions, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Pharmaceutically acceptable salts comprising an acidic moiety may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, silver hydroxide, ammonia or the like, or suitable non-toxic amines, such as lower alkylamines, hydroxy-lower alkylamines, cycloalkylamines, or benzylamines, or L- arginine or L-lysine. The term "solvate", as used herein, is intended to indicate a species formed by interaction between a compound, and a solvent such as water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N- dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidinone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof and the like. The term “hydrate”, as used herein, refers to a solvate when the solvent is water. Hydrates may further comprise one or more additional solvents. The composition may be formulated for administration in solid or liquid form such as sterile solutions, suspensions, sustained-release formulations, tablets, capsules, pills, powders, and granules. A composition of the invention (e.g. a solution or suspension) may comprise the conjugate at a concentration of no more than 500 μM, no more than 100 μM, no more than 50 μM, no more than 10 μM, or no more than 5 μM. In some embodiments the composition (e.g. a solution or suspension) comprises the conjugate at a concentration of from 100 μM to 2 M, from 500 μM to 1.5 M, from 0.001 M to 1.0 M, from 0.005 M to 0.8 M, from 0.01 M to 0.6 M, from 0.05 M to 0.5 M, or from 0.1 M to 0.4 M. It will be appreciated that the amount of conjugate present in a composition of the invention may depend on a number of factors, such as the age and / or weight of the subject, the general health of the subject, the type of radionuclide, the mode of administration, and whether the conjugate is intended for diagnosis or treatment. For example, a composition may be formulated so that a dosage of from 0.01 to 500 mg / kg, from 0.05 to 200 mg / kg or from 0.1 to 100 mg / kg can be administered. The composition may be formulated for oral or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, inhaled / aerosolized, intraarterial, intrathecal, intratumoral, intracystic, peritumoral, intraperitomeal, intraluminal, intrapleural) administration. When being administered orally, the composition can be in the form of a pill, tablet, or capsule. A composition formulated for parenteral administration may include an aqueous or non- aqueous solution (e.g. a sterile solution). The solution may contain one or more anti- oxidants, buffers, bacteriostats, or solutes. In some embodiments, the composition comprises a conjugate as described herein and at least one radiostabilizer. A radiostabilizer helps to prevent degradation of the conjugate due to radiation decay. Suitable radiostabilizers will be known to those skilled in the art. In some embodiments the radiostabilizer is selected from ethanol, gensitic acid, ascorbic acid and L- methionine. The composition may further comprise an aqueous medium, such as water or saline. The conjugates and compositions described herein find use as a diagnostic or imaging agent. A conjugate (or a composition comprising said conjugate) for use in a method of detecting or diagnosing cancer may comprise a compound according to the invention complexed with a radionuclide. The radionuclide may be one that is suitable for diagnostic imaging, such as PET or SPECT imaging. In some embodiments the radionuclide is selected from Al-18F,44Sc,64Cu,68Ga,86Y,89Zr,152Tb,47Sc,67Ga,67Cu,99mTc,111In,155Tb,175Yb,186Re and188Re. Those radionuclides that are suitable for PET imaging include: Al-18F,44Sc,64Cu,68Ga,86Y,89Zr,152Tb. Radionuclides that are suitable for SPECT imaging include:47Sc,67Ga,67Cu,99mTc,111In,155Tb,175Yb,186Re and188Re. It will be appreciated that some radionuclides that can be used for imaging (e.g. SPECT imaging) are also useful therapeutically. In some embodiments the radionuclide is68Ga. In some embodiments, the conjugate is68Ga-KK02. A conjugate of the compound of the invention with a radionuclide, particularly a conjugate comprising the compound KK02, has been observed to have much improved pharmacokinetics when compared to previously known18F-labeled PARP inhibitors. The conjugate demonstrated rapid clearance from major abdominal organs, such as liver, lung, spleen, pancreas, gastric and kidney as early as 30 minutes post-injection of the radiopharmaceutical. Advantageously, this allows imaging to be performed soon after a patient is administered with the imaging agent (e.g. <1 hour after injection) and reduces overall radiation exposure. Furthermore, the rapid clearance allows a wider therapeutic window for when the conjugate or composition is used as a medicament. In some embodiments, at least 90% of the conjugate is cleared from one or more or all of the major organs (i.e. the liver, lung, spleen, pancreas, stomach, kidney, small intestine, large intestine, skin, bone, blood, muscle, heart, brain) within 180 minutes, within 120 minutes, within 90 minute or within 60 minutes post-injection. In a further aspect, the invention provides a method of detecting cancer in a subject, said method comprising imaging a subject who has (previously) received a conjugate or a composition as described herein. It will be understood that the step of administering the conjugate or composition to the subject does not form part of this aspect of the invention. In addition to providing an initial diagnosis of cancer, the conjugates and compositions of the invention may find utility in monitoring the efficacy of a cancer treatment. For example, a method of monitoring the efficacy of a cancer treatment may comprise: imaging a subject who has received (i.e. been administered) a conjugate or a composition as described herein. The imaging may be carried out after the subject has received one or more treatments, or a course of treatments. For example, imaging may be carried out periodically to assess the progress of treatment. In some embodiments, the subject may have been treated with a conjugate or composition as described herein. In some embodiments, the subject is imaged using positron emission tomography (PET), magnetic resonance (MR) or single-photon emission computed tomography (SPECT). The skilled person will be familiar with suitable imaging protocols. In some embodiments, the subject is imaged a period of time after having been administered with the conjugate or composition. In some embodiments the period of time is no more than 3 hours, no more than 150 minutes, no more than 2 hours, no more than 90 minutes, no more than 1 hour, no more than 50 minutes, no more than 45 minutes, no more than 40 minutes, no more than 30 minutes, no more than 20 minutes, no more than 15 minutes, no more than 10 minutes, or no more than 5 minutes. However, it will be appreciated that the time period between administration of the conjugate or composition and imaging will be selected by the skilled person according to the type of imaging and / or the half life of the radionuclide. For example, in embodiments wherein the subjected is imaged using PET (e.g. using a conjugate as described herein, such as68Ga- KK02), the subject may be imaged no more than 60 minutes after having been administered with the conjugate, or a composition comprising the conjugate. After 60 minutes, the radioactivity measurable in many organs is decreased as the conjugate is cleared. Other radionuclides (such as177Lu, which can be used for SPECT imaging) have longer half- lives. Thus, in some embodiments, the subject may be imaged at least 1 hour, at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 16 hours or at least 24 hours after having been administered with the conjugate or composition. The invention also provides a conjugate or a composition as described herein, for use as a medicament. In particular, the invention provides the conjugate or the composition as described herein, for use in the treatment of cancer. As used herein, the term “treatment” refers to the decrease, prevention, delay, suppression, or elimination of any symptom of the cancer. The treatment is not required to cure the cancer but will provide a benefit in that the progression of the disease is delayed or prevented, one or more symptoms are ameliorated, the term of the disease is reduced, the subject’s quality of life is improved and / or life span is extended. For example, the treatment may result in a reduction in the number and / or size of tumors, or in the prevention of tumor growth. In a further aspect, the invention provides a method of treating cancer in a subject, the method comprising administering to the subject the conjugate or a composition as described herein. A conjugate (or a composition comprising said conjugate) for use in a method of treating cancer may comprise a compound according to the invention complexed with a radionuclide. The radionuclide may be one that is suitable for therapy. Radionuclides that are suitable for therapy will be known to the skilled person. The radionuclide may be an alpha, beta or auger emitter. In some embodiments the radionuclide is selected from47Sc,90Y,161Tb,169Er,175Yb,186Re,188Re,225Ac,64Cu,67Ga,111In,161Tb,165Er,175Yb and177Lu. In some embodiments the radionuclide is177Lu. In some embodiments, the conjugate is177Lu-KK02. In some embodiments the method comprises administering a therapeutically effective amount of the conjugate to the subject. A “therapeutically effective amount” is an amount which is sufficient to substantially improve at least one symptom associated with a disease or a medical condition. For example, in the treatment of cancer, an agent or compound that decreases, prevents, delays, suppresses, or arrests any symptom of the cancer would be considered therapeutically effective. An amount which is therapeutically effective will depend on a number of factors such as the type and severity of the cancer, and the weight and overall health of the subject. A suitable dose can be determined by the skilled person taking into account such factors. Single or multiple administrations of the conjugate or composition of the invention may be carried out with dose levels and dosage regime being selected by the treating physician. In some embodiments, the conjugates of the invention may be used in combination with other therapeutic agents (e.g. chemotherapeutic agents). The composition can be administered locally, for example by injection (e.g. intratumoral, intraarterial, intramuscular, intradermal or subcutaneous injection). Alternatively the composition may be administered orally or systemically (e.g. by intravenous injection or blood infusion). The invention also provides a conjugate or composition as described herein, for use in the manufacture of a medicament for the treatment of cancer. In some embodiments, the cancer is a PARP-expressing cancer. In some embodiments, the cancer is a PARP-1, a PARP-2 and / or a PARP-3 expressing cancer. In some embodiments, the cancer is a PARP-1 expressing cancer. In some embodiments, the cancer overexpresses PARP-1, PARP-2 and / or PARP-3. In some embodiments, the cancer overexpresses PARP-1. In some embodiments, the cancer has a mutation in BRCA. In some embodiments the cancer has a BRCA1 mutation, and / or a BRCA2 mutation. In some embodiments, the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, adrenocortical cancer, gastric cancer, endometrial cancer, hepatocellular cancer, leukaemia, lymphoma, non-Hodgkin’s lymphoma, uterine cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), kidney cancer, skin cancer, basal cell carcinoma, malignant melanoma, myeloma, ovarian cancer (including high grade serous ovarian cancer (HGSOC)), prostate cancer (including metastatic castration-resistant prostate cancer (mCRPC) and HRR-proficient mCRPC), pancreatic cancer, brain cancer (including neuroblastoma), sarcoma, head and neck cancer, cancer of the spleen, and bone marrow cancer. The subject may be a human or a non-human animal (e.g. a mammal). The invention further provides a kit comprising a compound as described herein and at least one radionuclide. In some embodiments, the at least one radionuclide is selected from177Lu,68Ga,64Cu,67Cu,67Ga,111In, Al-18F,89Zr,255Ac,86Y,90Y,186Re,188Re,44Sc,152Tb,161Tb,169Er,165Er,47Sc,155Tb,175Yb and99mTc. In some embodiments, the radionuclide is177Lu. In some embodiments, the radionuclide is68Ga. In some embodiments, the kit comprises at least two radionuclides. For example, one radionuclide may be suitable for diagnostic use (e.g.68Ga) and the other radionuclide may be suitable for therapeutic use (e.g.177Lu). It will be understood that any of the aspects and embodiments of the invention may be combined with any other aspect or embodiment in any combination, unless otherwise stated. Example 1 Here, we report the discovery of a radiotheranostic agent that is based on the potent PARPi olaparib. The precursor molecule KK02 forms stable complexes with68Ga and177Lu (“match- pair”) that are of useful for PARP-expressing cancers imaging using PET and MRT via β- radiation. In vitro evaluations of68Ga- and177Lu-KK02 using a panel of PARP-expressing cancer cell lines (prostate, pancreatic and breast cancers) demonstrated excellent binding specificity towards PARP-1, the main PARP isoform found to be overexpressed in these cancer cells. In addition,177Lu-KK02 is cytotoxic to a range of different PARP-1 expressing cancer cells, and holds promise for use as a PARP targeting radiotherapeutic agent across different cancer cells. The diagnostic companion68Ga-KK02 displays fast organ clearance and good tumor-to-background uptake in vivo using both healthy and triple-negative breast cancer (TNBC) bearing xenografts. Taken together the ‘match-pair’68Ga- and177Lu-KK02 demonstrate potential for use as a radiotheranostic agent for PARP expressing cancers. Materials and methods General All general reagents and consumables were purchased from commercial suppliers (Merck, Thermo Fisher Scientific, VWR, Bio-Rad) and were of analytical grade or higher, and were used without further purification unless otherwise stated. Tacn, NOTA-bis(tert-butyl)ester and NODAGA-tris(tert-butyl)ester were purchased from Macrocyclics (Plano, TX). Deionized water was prepared on site using a Millipore Direct-Q® 3UV water purification system. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker 500 (500.13 MHz), and were internally referenced to the appropriate solvent peak (CDCl3, DMSO-d6, D2O or MeOD). Mouse (#M5905) and human serum (#H6914) were purchased from Merck. HPLC analysis were performed on Agilent 1260 series HPLC with quadrupole pump, vacuum degasser, variable wavelength detector (20 µL standard loop, set to 254 nm), radioactivity detector (NaI PMT, LabLogic) and manual syringe injector (Rheodyne®7725). The flow rate was 1 mL / min using HPLC gradient method 1 or 2, and gradients included 5 min of equilibration at 10% of concentration B. Mobile phase A was water with 0.1% TFA and mobile phase B was acetonitrile with 0.1% TFA. For method 1, concentration of B increased from 10 to 90% (0 – 12 min). For method 2, concentration of B increased to 40% (0 – 3 min), remained at 40% (4 – 9 min) then subsequently increased to 90% (10 – 12 min). The HPLC column was a Phenomenex Gemini®3 µm 110 Å C-18 analytical column (4.6 × 150 mm). All reactions were carried out under the atmosphere unless otherwise stated. Chemistry S1 The compound was synthesized using a modified literature procedure (Eisenweiner KP, Powell P, Macke HR. Bioorg. Med. Chem. Lett., (2000).18(10):2133 – 2135). To a vigorously stirred aqueous solution of L-glutamic acid (10 g, 68 mmol), MgSO4 (8.18 g, 68 mmol) and benzyl alcohol (125 mL) was added tetrafluoroboric acid-diethyl ether (10 mL, 73 mmol) and the resultant mixture was stirred at RT overnight. THF (500 mL) was added to the mixture and the solution was filtered through a pad of Celite / activated charcoal. Triethylamine (147 mmol, 20.5 mL) was added to the filtrate, to which the off-white solid was formed and collected. The solvent was further concentrated in vacuo to yield more product. The compound was triturated with ethyl acetate (3 × 10 mL) to afford the product as white solid, and NMR data was consistent with the reported values. Yield: 12 g, 74%. S2 The compound was synthesized using a modified literature procedure (Eisenweiner KP, Powell P, Macke HR. Bioorg. Med. Chem. Lett., (2000). 18(10):2133 – 2135). To a pre- cooled solution of S1 (2.3 g, 9.7 mmol), NaBr (2.99 g, 29.1 mmol) and 1N HBr (45 mL, 17.3 mmol) at 0 ^C was added NaNO2 (0.52 g, 7.5 mmol) in small portions over 30 min. The mixture was stirred at 0 ^C for another 2 h, concentrated H2SO4 (0.87 mL) was added to the solution followed by diethyl ether (10 mL). The organic layer was separated, and the mixture was further extracted with diethyl ether (3 × 10 mL). The combined organic fractions were dried over MgSO4and the solvent was removed in vacuo. After purification on silica, with ethyl acetate / hexane (4 / 1 v / v) as the eluent, the product was obtained as a yellow oil, and NMR data was consistent with the reported values. Yield: 1.5 g, 51%. The compound was synthesized using a modified literature procedure (Eisenweiner KP, Powell P, Macke HR. Bioorg. Med. Chem. Lett., (2000).18(10):2133 – 2135). To a solution of S2 (1.5 g, 5.1 mmol) in chloroform (10 mL) was added a solution tert-butyl 2,2,2- trichloroacetimidate (2.43 g, 11.2 mmol) in cyclohexane (10 mL) over 20 min. A small portion of DMF was added into the mixture until the solution turned clear followed by addition of boron trifluoride-diethyl ether solution (35 µL). The mixture was stirred at RT for 3 days, the solvent was removed in vacuo and the residue was extracted with hexane (3 × 50 mL). The combined organic fractions were dried over MgSO4 and the solvent was removed in vacuo. After purification on silica, with ethyl acetate / hexane (4 / 1 v / v) as the eluent, the product was obtained as a colorless oil, and NMR data was consistent with the reported values. Yield: 0.5 g, 28%.1H NMR (CDCl3): ^ 1.49 (s, 9H, tBu-CH3), 2.26 – 2.54 (m, 2H, CH2), 2.57 – 2.60 (m, 2H, CH2), 4.25 – 4.28 (t, 1H,3JHH = 6.8 Hz, CH), 5.16 (s, 2H, CH2), 7.38 (s, 5H, Aryl-CH2) ppm. S4 To a mixture of NOTA-bis(tert-butyl) ester (0.217 g, 0.52 mmol) and S3 (0.187 g, 0.52 mmol) in acetonitrile (20 mL) was added K2CO3 (0.109 g, 0.79 mmol). The resulting solution was heated at 60 ^C overnight. The solution was filtered while hot, and the solvent was removed in vacuo to afford a brown oil. After purification on silica, with ethyl acetate / hexane (4 / 1 v / v) as the eluent, the product was obtained as a colorless oil. Yield: 0.16 g, 48%.1H NMR (CDCl3): ^ 1.45 (s, 27H, tBu-CH3), 1.86 – 2.02 (m, 2H, CH2), 2.50 – 2.69 (m, 2H, CH2), 2.71 – 2.93 (m, 12H, CH2), 3.16 – 3.19 (t, 1H,3JHH= 6.8 Hz), 3.30 (s, 4H, CH2), 5.13 (s, 2H, CH2), 7.28 – 7.36 (m, 5H, Aryl-CH2) ppm. S5 To a solution of S4 (0.16 g, 0.25 mmol) in methanol (10 mL) under an atmosphere of H2was added a suspension of Pd / C (8 mg, 7.9 µmol) in water (1 mL). The mixture was stirred at RT overnight, filtered through a pad of Celite and the solvent was removed in vacuo to afford an off-white residue. After purification on silica, with ethyl acetate / methanol (from 10 / 0 to 9 / 1 v / v) as the eluent, the product was obtained as a white solid. Yield: 0.11 g, 77%.1H NMR (CDCl3): ^ 1.42 (s, 27H, tBu-CH3), 1.91 – 2.09 (m, 2H, CH2), 2.47 – 2.56 (m, 2H, CH2), 2.90 – 3.08 (m, 12H, CH2), 3.33 – 3.48 (m, 5H, CH2and CH) ppm. COOH could not be observed due to the exchange of OH to OD in solution. S6 To a vigorously stirred solution of S5 (61 mg, 0.112 mmol), triethylamine (24 µL, 0.168 mmol) and HBTU (47 mg, 0.123 mmol) in DMF (1 mL) was added a solution of 4-(4-Fluoro-3- (Piperazine-1-carbonyl)Benzyl) Phthalazin-1(2H)-One (41 mg, 0.112 mmol) in DMF (1 mL). The resulting mixture was stirred at RT for 2 days and diluted with water (20 mL). The aqueous layer was extracted with DCM (3 × 20 mL), the combined organic fractions were dried over MgSO4and the solvent was removed in vacuo to afford an off-white residue. After purification on silica, with ethyl acetate / methanol (from 10 / 0 to 9 / 1 v / v) as the eluent, the product was obtained as a colourless oil. Yield: 60 mg, 60%.1H NMR (CDCl3): ^ 1.44 (s, 27H, tBu-CH3), 2.04 – 2.13 (m, 3H, CH2), 2.82 – 2.84 (m, 2H, CH2), 3.01 – 3.84 (m, 24H, CH2 and CH), 4.29 (s, 2H, CH2), 7.01 – 7.02 (m, 1H, Aryl-CH), 7.33 – 7.34 (m, 2H, Aryl- CH), 7.48 – 7.79 (m, 3H, Aryl-CH), 8.42 – 8.43 (m, 1H, Aryl-CH), 11.15 (s, 1H, CONH) ppm. KK02 To a vigorously stirred solution of S6 (60 mg, 0.067 mmol) in DCM (5 mL) was added a solution of TFA (1 mL) in DCM (1 mL) in dropwise. The mixture was stirred at RT overnight and the solvent was removed in vacuo to afford a yellow residue. The crude product was triturated with diethyl ether (3 × 5 mL), and the residue was further recrystallized from a mixture of acetonitrile and diethyl ether to give the product as a white solid. Yield: 35 mg, 72%.1H NMR (MeOD): ^ 2.01 – 2.18 (m, 2H, CH2), 2.62 – 2.75 (m, 2H, CH2), 2.85 – 3.29 (br, 12H, CH2and CH), 3.31 – 3.85 (m, 13H, CH2and CH), 4.40 (s, 2H, CH2), 7.01 – 7.02 (m, 1H, Aryl-CH), 7.33 – 7.34 (m, 2H, Aryl-CH), 7.48 – 7.79 (m, 3H, Aryl-CH), 8.42 – 8.43 (m, 1H, Aryl-CH) ppm. COOH and CONH could not be observed due to the exchange of OH to OD in solution. nGa-KK02 The pH of a solution of KK02 (30 mg, 0.041 mmol), Ga(NO3)3 (10.6 mg, 0.041 mmol) in water (5 mL) was adjusted to pH 3 – 4 with an aqueous solution of 1 M HCl. The mixture was stirred at RT overnight and the solvent was removed in vacuo to afford a white residue. The crude product was recrystallized from a mixture of methanol and diethyl ether to give the product as a white solid. Yield: 17 mg, 52%. Radiochemistry All instruments for measuring radioactivity were calibrated and maintained in accordance with previously reported routine quality control procedures (P. Zanzonico, 2008, JNM, 49, 1114). Water and HCl (Ultrapur), NaOH and ammonium acetate (99.99% trace metal) were purchased from Merck.177Lu was purchased from Diagnostic Imaging Ltd. The68Ge / 68Ga generator (ITG GmbH Germany, 1905 MBq at calibration date) was eluted with 0.05 M HCl (4 mL) in 4 × 1 mL fractions, and the fraction containing the peak radioactivity was used for radiochemistry. For chelex buffer preparation, Chelex-100 resin (5g) was added to 0.1 M ammonium acetate buffer (pH 4.5, 100 mL) and stirred overnight at room temperature. Aliquots of the buffer were removed for radiolabeling experiments. A C-18 solid phase extraction (SPE) cartridge column (Waters Corp., #WAT020515) was activated by sequentially injection of ethanol (5 mL) followed by water (10 mL). Radioactivity measurements were performed on a CAPINTEC CRC®-15R Dose Calibrator with calibration factor set to 416 and 450 × 10 for68Ga and177Lu, respectively. Radio-TLC analysis was performed on AR-2000 radio-TLC plate reader (Eckert & Ziegler with WinScan 2 software). Radioactive reactions were monitored using silica-gel impregnated glass microfiber instant thin-layer chromatography (ITLC-SG) paper (Agilent) and mobile phase 0.1 M sodium citrate buffer. Radiochemical conversion (RCY) was determined by integrating peak area of68Ga or177Lu-labeled compound (Rf= 0.4–0.6) and 'free'68Ga or177Lu (Rf= 1.0) obtained by radio- TLC plate reader. The radio-HPLC analysis was performed on a HPLC system using either of the HPLC gradient methods as described above. All gamma counting was performed on a Perkin Elmer 2480 WIZARD2or Hidex Automatic Gamma Counter. A stock solution of KK02 precursor was prepared in ultrapure water for radiolabeling experiments. For68Ga labeling, aliquots of chelator stock solution were mixed in the 1 M ammonium acetate buffer (pH 3.9) to provide solutions with final concentrations ranging from 5 μM to 500 μM (5 μM, 10 μM, 50 μM, 100 μM, 500 μM).68GaCl3(11–14 MBq in 0.05 M aqueous HCl) was added and the reaction mixture was allowed to incubate at 90 °C, After 10 minutes, the reaction solution was analyzed by radio-HPLC. Similar procedures were applied to177Lu labeling (150–250 MBq in 0.1 M aqueous HCl), except that chelex 0.1 M ammonium acetate buffer (pH 4.5) was used and reaction was performed for 1 h. For chelex buffer preparation, Chelex-100 resin (g / L, wet weight) was added to 0.1 M ammonium acetate buffer (pH 4.5) and stirred overnight at room temperature. Aliquots of the buffer were removed for radiolabeling experiments. PARP-1 chemiluminescent binding assay A commercially available assay (Trevigen, Gaithersburg, MD; catalog no 4671-096-K) was used to measure PARP-1 catalytic activities in vitro, in a cell-free assay, in the presence of varying concentrations of KK02, according to the manufacturer’s instructions. Elacridar was used as a negative control. Cell culture Breast cancer (MDA-MB-231 and MDA-MB-436) cells were purchased from ATCC (UK) and maintained in in high glucose Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS, Gibco), 2 mM L-glutamine, 100 units / mL penicillin, and 0.1 mg / mL streptomycin (Gibco). Pancreatic adenocarcinoma (AsPC1 and PSN1) and prostate cancer (22Rv1 and LNCaP) cells were purchased from ATCC (UK) and maintained in Roswell Park Memorial Institute (RPMI) supplemented with 10% fetal bovine serum (FBS, Gibco), 2 mM L-glutamine, 100 units / mL penicillin, and 0.1 mg / mL streptomycin (Gibco). Cells were grown under a humidified environment at 37°C and 5% CO2. Cells were harvested and passaged using trypsin-EDTA solution. Cells were used for no more than 15 passages following resuscitation from liquid nitrogen storage. All cells were authenticated by the provider and Short Tandem Repeat (STR) profiling and tested regularly for the absence of mycoplasma. In vitro uptake and specificity of 68Ga-KK02 and 177Lu-KK02 MDA-MB-231, MDA-MB-436 AsPC1, PSN1, 22Rv1 and LNCaP (1 × 105cells / well), were prepared using trypsin-EDTA and seeded separately in 24-well plates containing growth medium and allowed to adhere for at least 20 h. Cells were washed and exposed to unlabeled PARP inhibitors (0 or 100 μM, in a total of 270 μL growth medium) for 30 min at 37°C. Then,68Ga-KK02 (30 μL, 360 kBq, Am= 3.3–4.9 MBq / nmol) or177Lu-KK02 (30 μL, 100 kBq, Am= 22–49.8 MBq / nmol) was added, and the cells incubated at 37 °C for a 30 min. Cell culture medium was removed, and the cells washed with PBS. Cells were lysed using RIPA buffer (950 mM Tris pH 8.0, 1% NP40, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulphate, and 150 mM sodium chloride) for 15 min at room temperature, and the amount of68Ga or177Lu in cell lysates was measured using an automated gamma counter (Wizard, PerkinElmer). Alongside, counting of cells prior to the68Ga-KK02 or177Lu-KK02 treatment was performed using automated cell counter. In a separate experiment, cells were prepared in a similar manner, but cells were washed and exposed to177Lu-KK02 (100 kBq, Am = 22–49.8 MBq / nmol) at 37°C for different intervals (1–180 min). The amount of177Lu in cell lysates was measured as above. Separate again, cells were exposed to177Lu-KK02 (100 kBq, Am = 22–49.8 MBq / nmol) for 30 min at 37°C, washed with PBS, supplied with fresh growth medium, and the amount of177Lu associated with cells measured after varying intervals as above. Cell viability assay and quantification of yH2AX expression AsPC1, PSN1, 22Rv1, (1 × 105cells / well), were prepared using trypsin-EDTA and seeded separately in 24-well plates containing growth medium and allowed to adhere for at least 20 h. Cells were washed and exposed to none or increasing amounts of177Lu-KK02 (0–100 kBq, Am = 22–49.8 MBq / nmol), and the cells incubated at 37°C for a 1 h. After washing with PBS, cells were supplied with fresh growth medium for another 24 h incubation at 37°C. Cell viability and DNA double strand break damage of treated cells at 24 h post-treatment were measured via flow cytometry. Cells were harvested using trypsin-EDTA solution and washed with FACS buffer (PBS, 2% FBS, 1 mM EDTA, 0.1% NaN3) and centrifuged at 500×g for 5 min. Immunostaining was performed using the Foxp3 / transcription factor staining buffer set (eBioscienceTM, USA). Intracellular staining was conducted in permeabilization buffer for 30 min at 4°C in the dark using the following antibodies: anti-γH2AX antibody (JBW301, 1:800), which was used to quantify DNA double strand break damage, and fixable viability dye ef780 (1:4000; eBioscienceTM; 65-0865-14), which was used to discrimination between live and dead cells. Fixation of immunostained cells was performed using the Foxp3 Transcription Factor Staining Buffer Set (eBioscienceTM, 00-5523-00) for 15 min at RT. Flow cytometry was conducted using a CytoFLEX flow cytometer (Beckman Coulter, USA), with appropriate lasers and filters, positive and negative controls. Data were analyzed using FlowJoTM(Tree Star Inc., Beckton Dickinson Biosciences, USA). Colony Formation Assay After harvesting using Accutase (Innovative Cell Technologies, Inc.), aliquots of 1 × 105cells and 2 × 105cells (MDA-MB-231 and MDA-MB-436, respectively), in 0.2 mL of DMEM in 0.5 mL Eppendorf tubes, were exposed to none or increasing amounts of177Lu-KK02 (0.01–100 kBq, Am= 31.8 MBq / nmol, total amount of complex: 0.31–3100 fmol) at 37 °C for 3 h. After incubation, cell suspensions were diluted to 3 mL of growth medium, with a fraction of the cells (1.5 mL, 5000 cells) seeded in duplicate in 6-well plates before medium was added to bring the total to 3 mL. Two weeks later, the number of colonies (>50 cells) was measured after washing and staining using crystal violet (1 mg / L in a 1:1 water:methanol). In vivo imaging and ex vivo biodistribution of 68Ga-KK02 and 177Lu-KK02 All animal procedures were performed in accordance with the United Kingdom Home Office’s Guidance on the Operation of Animals (Scientific Procedures) Act 1986; Or, with the Committee of the Use of Live Animals in Teaching and Research at the University of Hong Kong, and the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. Local ethical committee approval was obtained (PPL PA1B5C52F, University of Oxford). Female immunocompromised Balb / c nude (OlaHsd-Foxn1nu) and male immunocompetent FVB mice, aged 4-6 weeks were purchased from Envigo (UK). Animals were housed in individually ventilated cages, up to 6 per cage, in an artificial day-night cycle facility. Food and water were provided ad libitum. MDA-MB-231 or MDA-MB-436 cells were harvested using trypsin-EDTA, washed twice with PBS, and reconstituted in PBS:Matrigel® Matrix High Concentration (1:1). Cell suspensions containing 1 × 107cells were injected subcutaneously into the flank and allowed to form tumors. Tumor sizes were measured twice per week by caliper, and tumor volumes were calculated as volume (mm3) = L × W2× 0.5, where L and W represent the largest and smallest diameters, respectively. 68Ga-KK02 PET / MR imaging: Tumor naïve mice (n = 4) were anaesthetized via inhalation of 5% isoflurane / oxygen gas mixture and placed on a pre-warmed mouse bed in the prone position. Dynamic PET / MR imaging was performed immediately after the intravenous injection of68Ga-KK02 (11.1–18.5 MBq, Am= 3.3–4.9 MBq / nmol) over 2 h using nanoScan PET / MRI system (Mediso Medical Imaging Systems Ltd., Budapest). Mice were maintained using 2% isoflurane / oxygen throughout the duration of image acquisition. In the case of MDA-MB-231 and MDA-MB-436 xenografts (n = 3 / group), static PET / MR imaging was performed when tumors reached 600–800 mm3in size, at 1 h after the injection of68Ga- KK02 (5.55–9.25 MBq, Am= 3.3–4.9 MBq / nmol). For blocking studies, an excess of olaparib (0.5 mg) was administrated via intraperitoneal injection 30 minutes prior to68Ga-KK02 injection. T2-weighted MRI scans were performed for anatomical information and attenuation correction of PET images. PET images were reconstructed using the vendor’s reconstruction algorithm Tera-Tomo 3D (ordered subset expectation maximization), with radionuclide decay, normalization, random, scatter, attenuation and dead time corrections applied to the data, resulting in a matrix of 0.3 mm3. The PET and MR images were co-registered automatically and data analyses were performed using InterView Fusion version 3.03. 177Lu-KK02 SPECT / CT imaging: MDA-MB-436 tumor bearing mice were aneasthetized as described, and dynamic SPECT / CT imaging was performed when tumors reached 100–200 mm3in size, immediately after the intravenous injection of177Lu-KK02 (8–11.2 MBq, Am = 22–49.8 MBq / nmol) over 1 h using VECTor4 system (MIILabs, Tokyo, Japan) equipped with an ultra-high-resolution rat or mouse collimator (1.8 mm). For blocking studies, an excess of olaparib (0.5 mg) was administrated via intraperitoneal injection 30 minutes prior to177Lu- KK02 injection. Cone-beam CT scans (55 kV, 0.19 mA) were performed for anatomic reference and attenuation correction of SPECT images. SPECT images were reconstructed using U-SPECT-Rec3.22 software (MILabs, Japan), which applied a pixel-based algorithm, ordered-subset expectation maximization, with 128 subsets, 4 iterations and a 0.6 mm3voxel size for177Lu (energy window settings, 186–216 keV). Reconstructed SPECT and CT images were co-registrated automatically and data analyses were performed using PMOD version 3.37 (PMOD Technologies) (Fig.27). For ex vivo biodistribution, tumor naïve mice (n = 4 / timepoint) were intravenously administrated with either68Ga-KK02 (1.85–7.4 MBq, Am = 3.3–4.9 MBq / nmol, using female nude mice) and culled at 5, 15, 30, 60, 120 and 180 mins; or177Lu-KK02 (2.1–4.6 MBq, Am = 22–49.8 MBq / nmol, using male FVB mice) and culled at 1, 2, 24 and 48 h (Fig. 26). For MDA-MB-436 xenografts, mice were culled at 60 min after68Ga-KK02 injection (5.6–9.3 MBq, Am = 3.3–4.9 MBq / nmol), with or without olaparib and talazoparib (0.5 mg) administration (n = 3 / group) (Fig. 25). Similar procedures were applied for177Lu-KK02 experiments (8–11.2 MBq, Am= 22–49.8 MBq / nmol) (Fig. 28). Tissues of interest were collected and percentage of injected activity per gram of tissue (%ID / g) was determined using an automated gamma counter (Wizard, PerkinElmer). Localization of68Ga-KK02 or177Lu-KK02 in MDA-MB-436 tumors was determined ex vivo using autoradiography performed on frozen tumor sections (10–25 μm). The frozen tumor sections treated with68Ga-KK02 (25 μm) or177Lu-KK02 (10 μm) were exposed to storage phosphor screens at - 20°C for 1 h or 2 h, respectively. The phosphor screens were subsequently scanned by Amersham™ Typhoon™ Biomolecular Imager or PerkinElmer’s Cyclone® Plus Imager, respectively, to generate images for these tumor sections (Fig.29). In Vivo 177Lu-KK02 Therapy Studies Mice bearing MyC-CaP (murine prostate cancer model) allografts, with average tumor sizes of 50–150 mm3, were randomly grouped into cohorts and intravenously injected with177Lu- KK02 (60 MBq in 100 ^L PBS, Am = 22–49.8 MBq / nmol, n = 3 / group) or vehicle control (in 100 ^L PBS, n = 5 / group). Mice were monitored 2–3 times per week, with study endpoints at 21 d after initiation of treatment (i.e. corresponds to tumor size of <800 mm3) or weight loss of more than 15% (Fig. 30). Upon culling, bone marrow cells were collected from both femurs for cell-suface staining that was conducted in FACS buffer for 30 min at 4°C in the dark using the following antibodies: PE / Cyanine5 anti-mouse CD11b antibody (1:100; BioLegend®; 101209), which was used to determine the percentage of total myeloid cells present in both177Lu-KK02-treated and vehicle control mice (Fig. 31), and LIVE / DEADTMFixable Green (1:1000; ThermoFisher; L34969), which was used to discrimination between live and dead cells. Fixation of immunostained cells was performed using the 4% PFA solution for 15 min at RT. Flow cytometry was conducted using a Cytek Aurora – spectral flow cytometer (Cytek®Biosciences, USA), with appropriate lasers and filters, positive and negative controls. Data were analyzed using FlowJoTM(Tree Star Inc., Beckton Dickinson Biosciences, USA). Statistical analysis All statistical analyses and nonlinear regression were performed using GraphPad Prism v8 or higher (GraphPad Software, San Diego, CA, USA). Data were tested for normality and analyzed as appropriate by 1 or 2-way analysis (ANOVA), with Dunnet posttests to calculate the significance of differences between groups for multiple comparisons. All data were obtained at least in triplicate, and results are reported as mean ± standard deviation (SD), unless stated otherwise. Results KK02 is specific to PARP-1 and precursor to bind 68Ga and 177Lu To develop a suitable PARP targeting theranostic agent, we first modified the PARPi olaparib to incorporate a NODAGA chelator . Olaparib was chosen due to the excellent specificity against PARP-1 and PARP-2. The resulting precursor KK02 retains excellent PARP-1 specificity (IC50= 9.1 nM) (Fig.1) that is comparable to the parent molecule Olaraparib (IC50= 5 nM), and can be readily incorporated with either68Ga or177Lu for radiotheranostic application. Radiosynthesis of 68Ga- and 177Lu-KK0268Ga-KK02 was prepared via addition of68GaCl3to a solution of KK02 (10 nmol) in ammonium acetate buffer (1 M, pH 3.8) at 90 ^C for 10 minutes, with good radiochemical purity (RCP) of >99% and non-decay corrected radiochemical yield (RCY) of 39–58% (n = 7) after purifications. The identity of68Ga-KK02 was confirmed by radio-HPLC via the co- injection of a mixture of68Ga-KK02 and ‘cold’nGa-KK02, where the peak maxima of the radioactivity and UV absorbance coincided (Fig. 2). Further screening and optimization experiments suggested that >10 nmol of KK02 is required to achieve RCY of >90%, with molar activities (Am) of 3.3–4.9 MBq / nmol were used for subsequent in vitro and in vivo studies (Fig.3).68Ga-KK02 displayed excellent stability in PBS and saline for 3 h. Similarly, the radiopharmaceutical showed no degradation up to 3 h of incubation in human serum, indicating the outstanding in vitro stability (Fig.4). Radiolabeling of KK02 (5 nmol) with177LuCl3 was performed in chelex ammonium acetate buffer (0.1 M, pH 4.5) at 90 ^C for 60 mins, which was confirmed by iTLC with good RCP (>99%) and RCY (up to 74–78%, n = 5, non-decay corrected), and Am= 22–49.8 MBq / nmol (Fig.5). As expected,177Lu-KK02 exhibits excellent stability in PBS, saline and mouse serum (Fig. 6). More importantly, the radiopharmaceutical displays exceptional stability in mouse serum, with >90% of177Lu-KK02 retained after 7 days of incubation which is not observed in other previously reported177Lu-NOTA based radiotracers. 68Ga- and 177Lu-KK02 uptake and binding specificity in TNBC cells To demonstrate PARP targeting, we first determined the PARP-1 expression levels in a panel of triple-negative breast cancer (TNBC) cells by Western blotting. The results showed that PARP-1 expression is higher in MDA-MB-436 cells than in MDA-MB-231 cells (Fig. 7A and 7B), and both cell lines were used for subsequent comparisons.68Ga-KK02 was taken up within 30 min by both MDA-MB-231 and MDA-MB-436 cells, where MDA-MB-436 revealed a significant higher uptake than MDA-MB-231 cells (P < 0.01) (Fig. 8). These results are consistent with the relative PARP-1 expression levels in these cells as observed by Western blot. Cell-associated uptake of68Ga-KK02 in both MDA-MB-231 and MDA-MB-436 cells could be blocked by addition of a large excess of cold, unlabeled olaparib (P < 0.05), suggesting the high specificity of68Ga-KK02 to PARP binding sites. (Fig. 9 and Fig.10). In MDA-MB-436 cells, similar blocking efficiency could be observed using an excess of other structurally different PARPi such as talazoparib and rucaparib (all P < 0.001) (Fig.9 and Fig. 10), further demonstrating the excellent binding selectivity of68Ga-KK02 to PARP enzymes. The uptake of177Lu-KK02 was also evaluated in both MDA-MB-231 and MDA-MB-436 cells. Increased cellular uptake (~1.5 folds increase between 1 and 120 min) was observed when cells were exposed to177Lu-KK02 for longer periods of time in both cell lines, showing the highest uptake at 120 min post exposure to the radiopharmaceutical (Fig.11). Similar to the68Ga-KK02 findings, a higher177Lu -KK02 uptake was observed in the MDA-MB-436 than MDA-MB-213 cells, and could be explained by a higher PARP-1 expression level in MDA- MB-436 cells. The addition of excess and structurally different PARPi (veliparib, talazoparib, rucaparib and olaparib) were able to significantly reduce the177Lu-KK02 uptake in both cell lines (Fig.12). Of note is a greater blocking efficiency was found in the MDA-MB-436 (all P < 0.001) than in MDA-MB-231 cells (all P < 0.05), which again is due to the lower PARP-1 expression level in the MDA-MB-231 cells than MDA-MB-436 cells as determined by Western blot (Fig.7A). 177Lu-KK02 uptake, binding selectivity, retention and cytotoxicity in different PARP-1 expressing cancer cells To further evaluate PARP targeting capability of177Lu-KK02, a series of different PARP-1 expressing cancer cells such as pancreatic ductal adenocarcinoma cell lines (AsPC1, PSN1) and prostate cancer cell lines (22Rv1, LNCaP) were exposed to177Lu-KK02 in vitro.22Rv1 showed the highest uptake at 30 min after initial exposure of the cells to177Lu-KK02, whereas AsPC1 displayed the lowest among these cell lines (all P < 0.001) (Fig.13 and Fig. 14). These results agreed with the varying PARP-1 expression in these cells as observed from public human genome database, suggesting that177Lu-KK02 uptake is PARP-1 dependent regardless of cancer cell types (Fig. 13 and Fig. 14). Consistent with earlier findings in TNBC cell lines,177Lu-KK02 was taken up within 15 min by AsPC1, PSN1, 22Rv1 and LNCaP cells, while showing the highest uptake at 120 min after initial exposure to177Lu- KK02 (Fig. 15). Similarly, binding selectivity of177Lu-KK02 was evaluated using these cell lines, via blocking with structurally different PARPi (veliparib, talazoparib, rucaparib and olaparib). As expected, significant reduction of177Lu-KK02 uptake was found in the presence of an excess of these PARPi across all cell lines, indicating the substantial binding of177Lu- KK02 to PARP enzymes (all P < 0.01) (Fig.16). Retention assays were also performed to probe the binding properties of177Lu-KK02 towards PARP in both 22Rv1 (high PARP-1 expression) and PSN1 (low PARP-1 expression) cells. The results showed that177Lu-KK02 retained in cells up to 48 h after removal of the radiopharmaceutical, with 22Rv1 retaining more177Lu-KK02 than PSN1 (~2 folds in excess) and positively correlated with the PARP-1 expression levels (Fig.17). A relatively fast influx of177Lu-KK02 could be observed within the first 30 min followed by slow efflux over the next 48 h in both cell lines. In addition, 22Rv1, PSN1 and AsPC1 cells treated with increasing radioactivity of177Lu-KK02 (up to 100 kBq) all showed significant cell death as measured by flow cytometry (all P < 0.05, except P < 0.01 for 22Rv1). The findings were consistent with the increasing trend of ^H2AX expression observed in these treated cells, indicating a significant DNA damage upon exposure to177Lu-KK02 as low as 0.1 kBq in all cells (Fig.19). In addition, the clonogenic survival of both MDA-MB-231 and MDA-MB-436 cancer cells was reduced by exposure to177Lu-KK02 at activity levels as little as 0.1 kBq (Fig 20). The efficacy was significantly more pronounced in the higher PARP-1 expressing MDA-MB-436 cells compared to the lower PARP-1 expressing MDA-MB-231 cells in vitro (P = 0.049), suggesting that cancer cells with higher PARP expression may be more responsive towards177Lu-KK02 treatment. Collectively, these results demonstrate the in vitro cytotoxicity of177Lu- KK02 across different PARP-1 expressing cancer cell lines and that177Lu-KK02 could be a useful radiotherapeutic agent for a broad range of PARP-expressing cancers. Pharmacokinetics of 68Ga-KK02 in tumor-naïve and tumor-bearing mice In vivo pharmacokinetics of68Ga-KK02 were first performed using tumor-naïve (BALB / c nude) mice (n = 4). Dynamic PET / MR imaging of BALB / c nude mice receiving an intravenous injection of68Ga-KK02 (11.1–18.5 MBq, Am = 3.3–4.9 MBq / nmol) revealed fast pharmacokinetics and a mixed hepatobiliary / renal clearance pattern (Fig. 21). The majority of68Ga-KK02 was cleared quickly from major abdominal organs such as liver, lung, spleen, pancreas, gastric and kidney as early as 40 min post-injection of radiopharmaceutical, indicating a low radioactivity retention in these organs and can potentially improve tumor detection in the abdominal area. Biodistribution experiments performed at multiple timepoints ranging from 5 to 180 min (n = 4 / timepoint) confirmed the clearance of most of the68Ga- KK02 radioactivity from healthy organs at 1 h (Fig.22), which is consistent with our imaging data. Moreover, rapid elimination and accumulation of68Ga-KK02 from blood, liver and kidney to intestinal regions were observed within 30 min post-injection, potentially allows68Ga-KK02 PET imaging to be performed at an early timepoint (< 1 h after injection). The desired in vivo pharmacokinetic profiles are not observed in any18F-based PARPi reported to date. To investigate the PARP targeting in tumor tissue, we performed PET / MR imaging using the subcutaneous tumor-bearing mice at 1 h after intravenous injection with68Ga-KK02 (5.55– 9.25 MBq). We chose both MDA-MB-436 (high PARP-1 expressing) and MDA-MB-231 (low PARP-1 expressing) xenografts (n = 3 / group) to compare their68Ga-KK02 tumoral and whole-body organs uptake in vivo. Consistent to our in vitro data, tumor uptake of68Ga-KK02 in high PARP-1 expressing MDA-MB-436 xenografts is significantly higher than that in low PARP-1 expressing MDA-MB-231 xenografts (tumor SUVmax= 0.98±0.26 vs 0.62±0.08, P = 0.044, Fig. 23 and Fig 24). Whereas the biodistribution and clearance pattern in both xenografts were similar to that in tumor naïve mice, showing hepatobiliary / kidney clearance with low radioactivity retention in abdominal organs. The in vivo specificity of this uptake was further illustrated by a significant decrease in tumor uptake after an injection of an excess of olaparib 30 min prior to68Ga-KK02 administration (tumor SUVmax= 0.98±0.26 vs 0.52±0.07, P = 0.043, Fig.25). Ex vivo biodistribution results were consistent with the imaging findings, showing a significant higher68Ga-KK02 uptake for MDA-MB-436 than MDA-MB-231 tumors (1.04±0.2 vs 0.55±0.15 %ID / g, respectively, P < 0.01), which was again significantly reduced in the presence of an excess of PARPi olaparib and talazoparib (0.48±0.10 and 0.40±0.06 %ID / g, respectively, P < 0.05 in all cases). Similar blocking effects were observed in PARP-expressing organs like liver, spleen and pancreas, further supporting the binding specificity of68Ga-KK02 towards PARP enzymes. Additionally, the biodistribution results for MDA-MB-436 xenografts also revealed good tumor-to-background ratios (T / B ratio): Bone (5.24±2.30), pancreas (4.92±1.05), muscle (3.88±2.18), salivary gland (3.45±0.64), lung (1.84±1.10), blood (1.63±1.21) at 1 h, demonstrating the feasibility of68Ga-KK02 for whole- body imaging of PARP-expressing cancers. SPECT / CT imaging and ex vivo biodistribution studies of 177Lu-KK02 in tumor-naïve and tumor-bearing mice Ex vivo biodistribution studies were performed in tumor-naïve (FVB) mice at various timepoints (1, 2, 24, 48 h, n = 4 / timepoint) to investigate the pharmacokinetics of177Lu-KK02 (Fig. 26). Similar to68Ga-KK02,177Lu-KK02 exhibited rapid blood clearance along with a mixed hepatobiliary / renal clearance pattern. Importantly, kidney uptake of177Lu-KK02 at early timepoints was evidently cleared at the later timepoints (1 h vs 48 h, 21.93±2.75 %ID / g vs 0.23±0.06 %ID / g, P < 0.001), suggesting low renal retention of the radiopharmaceutical after the administration of177Lu-KK02. The remaining organs, including liver and intestine (content) where177Lu-KK02 is being cleared, had <0.3 %ID / g at 48 h. To confirm the PARP targeting of177Lu-KK02 in tumor tissue, we performed SPECT / CT imaging and biodistribution studies using the MDA-MB-436 subcutaneous tumor-bearing mice (8–11.2 MBq, Am= 22–49.8 MBq / nmol, n = 3 / group). SPECT / CT imaging at 1 h was well-matched to the ex vivo biodistribution results observed in the tumor-naïve mice (hepatobiliary / kidney clearance, Fig. 27). Whereas the tumor uptake and specificity of177Lu-KK02 to PARP-1 expression were clearly demonstrated, showing a significantly lower uptake was observed in the presence of an excess of PARPi Olaparib (0.68±0.18 %ID / g vs 0.31±0.07 %ID / g at 1 h, P = 0.029, Fig. 28). Similarly, the excellent T / B ratios were observed: Muscle (4.37±1.40), pancreas (3.77±0.75), salivary gland (2.88±0.72), bone (1.71±0.28), and these results indicate low radioactivity retention in non-target tissues, underscoring that177Lu-KK02 possesses the desired characteristics and in vivo behavior for MRT applications. Additionally, in vivo specificity of KK02 was validated by autoradiograhy analysis of resected tumors, showing a higher radiotracer uptake naïve tumor than Olaparib pre-treated tumor sample. Collectively, KK02 shows great promise as a theranostic agent for PARP-1 expressing cancers and merits further development for clinical use. Efficacy of 177Lu-KK02 in prostate cancer mouse model A177Lu-KK02 MRT study was performed on the prostate cancer MyC-CaP tumor-bearing FVB (immunocompetent) mice. Mice were randomly divided into 2 cohorts: Treatment group with single injection of 60 MBq of177Lu-KK02 (n = 3) or control group with single injection of vehicle (n = 5). All animals were euthanized by study day 39, which corresponds to 21 days after injection with either177Lu-KK02 or vehicle, with tumor size of 600±150 mm3. Mice in the treatment cohort displayed a significant tumor growth delay after a single dose of177Lu-KK02 (P < 0.05, Fig.30). Mice were weighted and monitored for observable symptoms, including changes in behavior and appearance, to assess outward signs of toxicity, No weight loss or other abnormalities were found between the treatment and vehicle cohorts. To assess the hematopoietic toxicity, bone marrow was extracted, and the percentage of total myeloid cells was compared between the treatment vehicle cohorts, and again, no significant difference was observed between the two samples (Fig. 31). These results indicate that a single injection of high177Lu-KK02 therapeutic dose (60 MBq) is safe and tolerable in mice. Discussion The vast majority of PARP-targeting radiotheranostic agents reported to date are based on radio-halogens and have met with the similar resistance: A slow in vivo hepatobiliary clearance coupled with high retention in major organs with physiological PARP expression. Altogether these properties significantly limit their wide adoption as imaging probes, and more importantly, as radiotherapeutic agents, since prolonged retention of radioactivity in these organs could unintentionally lead to increased in radiotoxicity in healthy tissues. Here, we developed KK02 as a novel olaparib-based PARP inhibitor, which can conveniently radiolabeled with either68Ga (diagnostic) or177Lu (therapeutic) radionuclide, to serve as the ‘match-pair’ PARP-targeting radiotheranostic agent with good tumor uptake and specificity (binds specificity to PARP-1) and improved in vivo pharmacokinetics (lower radioactivity retention hence lower off-target toxicities). Both68Ga- and177Lu-KK02 displayed a similar in vitro uptake and binding specificity profiles across a panel of PARP-1 expressing cancer cell lines, suggesting that a change in radionuclide do not significantly perturb the targeting ability and binding specificity of radiopharmaceuticals towards its target. Additionally,68Ga- and177Lu-KK02 is readily taken up by different cancer cells (30 min incubation with either radiopharmaceutical), with higher uptake observed in higher PARP-1 expressing cancer cells (22Rv1 being the highest and MDA-MB-231 the lowest among all the cell lines tested here). This further supports the feasibility of this ‘matched-pair’ radiotheranostic agent to for the diagnosis and treatment of PARP-expressing cancers. The in vitro cytotoxicity of177Lu-KK02 is apparent across different PARP-expressing cell lines, causing different degree of cell death and DNA damage (as evident by the accumulation of γH2AX expression) at different therapeutic dose. Furthermore, the remarkable ability of177Lu-KK02 to be retained in cells over a period of 48 h could potentially enhance the radiation dose absorbed by cancer cells, leading to improved therapeutic efficacy. Whether such observation is specific to certain cell lines, however, remains to be explored on a larger scale. In vivo, both68Ga-KK02 and177Lu-KK02 exhibit bioequivalence and possess an excellent pharmacokinetic profile – Good tumor uptake and fast non-target organs clearance. The results obtained in vivo and ex vivo biodistribution studies with KK02 suggest that the68Ga / 177Lu combination holds significant potential as a theranostic approach for PARP- expressing cancers and warrants further development for clinical translation. For example,68Ga-KK02 can be used as the companion diagnostic to permit patient stratification (pre- therapeutic imaging of PARP) and treatment monitoring of PARP inhibition (PARPi) therapy or177Lu-KK02 radionuclide therapy (post-therapeutic monitoring of PARP) to guide treatment decisions. Given that PARP is aberrantly expressed in many solid tumors, the development of PARP theranostics is expected to be beneficial in managing a wide range of cancers beyond those tested here (e.g. breast cancer: MDA-MB-436, prostate cancer: MyC-CaP, pancreatic cancer: PSN1). Current molecular biomarker assessments, such as BRCA1 / 2 mutation status, could not accurately predict the PARP inhibition treatment outcomes due to a lack of homologous recombination proficiency evaluation, and the sampling errors caused of intratumoral heterogeneity. Imaging of PARP using a PET tracer such as68Ga-KK02 enables whole-body imaging and analysis of primary and metastatic tumors, and may provide additional insights into tumor heterogeneity leading to more accurate treatment decisions. Furthermore, resistance to PARPi has become increasingly common in clinical practice and presents a significant therapeutic challenge. Although multiple efforts have been made to address PARPi resistance, the use of PARP radiotherapeutics could offer a new and effective treatment approach. For example, PARP-MRT with177Lu-KK02 has the potential to bypass known resistane mechanisms that occur downstream of PARP binding by directly delivering therapeutic levels of radiation to eradicate tumors. Since many therapeutic radiopharmaceuticals (i.e.177Lu / 225Ac-PSMA,177Lu / 90Y-DOTATATE) are primarily excreted through or retained in the kidneys, these organs become one of the major organs receiving high radiation absorbed doses, leading to radiation nephrotoxicity. Additionally, the accumulation of radioactivity in bone marrow could lead to hematopoietic toxicity, while the risk of hematologic toxicity may increase due to slow blood clearance. Together, these factors present a significant challenge to achieving successful MRT treatment outcomes, since dose-limiting radiogenic toxicity will significantly narrow the therapeutic window and limit the administered radiation dose required to achieve meaningful clinical outcomes. Radiation toxicity from MRT could be minimized due to the favourable in vivo behavior of KK02. A single injection of177Lu-KK02 can significantly slow tumor growth without causing noticeable radiation-related toxicity (i.e. hematopoietic toxicity), which can be explained by the low retention in non-target healthy tissues. Moreover, higher or multiple administrations of177Lu-KK02 is possible to deliver a more effective dose for improved efficacy. By combining comprehensive dosimetry and toxicity studies, an optimal dosing regime can be developed that maximizes efficacy with minimizing treatment toxicity.

Claims

Claims 1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or hydrate thereof:wherein: Z is a PARP inhibitor m is an integer from 0 to 6; n is an integer from 1 to 4; L is a bond, -O-, -S-, or -NH-; R1 is H, OH, C(O)OH, C(O)NH2 or C(O)NR3OH; each R2 is independently selected from OH and NR3OH; and each R3 is independently selected from H, CH3, and CH2CH3.

2. The compound of claim 1, wherein n is 1 or 2.

3. The compound of any of claim 1 or 2, wherein R1 is H or C(O)OH, optionally wherein R1 is C(O)OH.

4. The compound of any one of claims 1 to 3, wherein L is a bond or -O-, optionally wherein L is a bond.

5. The compound of any preceding claim, wherein each R2 is OH.

6. The compound of any preceding claim, wherein m is 0, 1 or 2, optionally wherein m is 0.

7. The compound of any previous claim, wherein Z is:and wherein: R4 is H, F, or Cl.

8. The compound of any preceding claim, wherein Z is:.

9. The compound of claim 1, having a structure selected from: ,,wherein m and R3are as defined in claim 1.

10. A conjugate comprising the compound of any one of claims 1 to 9 complexed with a radionuclide.

11. The conjugate of claim 10, wherein the radionuclide is selected from177Lu,68Ga, 64Cu,67Cu,67Ga,111In, Al-18F,89Zr,255Ac,86Y,90Y,186Re,188Re,44Sc,152Tb,161Tb,169Er, 165Er,47Sc,155Tb,175Yb and99mTc.

12. The conjugate of claim 11, wherein the radionuclide is177Lu.

13. The conjugate of claim 11, wherein the radionuclide is68Ga.

14. A composition comprising the compound of any one of claims 1 to 9, or the conjugate of any one of claims 10 to 13, and a pharmaceutically acceptable excipient.

15. The conjugate of any one of claims 10 to 13, or the composition of claim 14, for use as a medicament.

16. The conjugate of any one of claims 10 to 13, or the composition of claim 14, for use as a diagnostic or imaging agent.

17. The conjugate of any one of claims 10 to 13, or the composition of claim 14, for use in the treatment of cancer.

18. The conjugate for use according to claim 17 or 18, wherein the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, adrenocortical cancer, gastric cancer, endometrial cancer, hepatocellular cancer, leukaemia, lymphoma, non-Hodgkin’s lymphoma, uterine cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), kidney cancer, skin cancer, basal cell carcinoma, malignant melanoma, myeloma, ovarian cancer (including high grade serous ovarian cancer (HGSOC)), prostate cancer (including metastatic castration- resistant prostate cancer (mCRPC) and HRR-proficient mCRPC), pancreatic cancer, brain cancer (including neuroblastoma), sarcoma, head and neck cancer, cancer of the spleen, and bone marrow cancer.

19. A method of detecting cancer in a subject, said method comprising imaging a subject who has received the conjugate of any one of claims 10 to 13, or the composition of claim 14.

20. A kit comprising a compound according to any one of claims 1 to 9 and a radionuclide, optionally wherein the radionuclide is selected from17177Lu,68Ga,64Cu, 67Cu,67Ga,111In, Al-18F,89Zr,255Ac,86Y,90Y,186Re,188Re,44Sc,152Tb,161Tb,169Er,165Er, 47Sc,155Tb,175Yb and99mTc.

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