1. THERANOSTICS 2. Combination of two words: Therapeutic + Diagnostic Sometimes interchangably refered to asTheragnostics Use of radionuclide-labeled agents thatspecifically permit us to diagnose disease inindividuals and then use identical or closelyrelated agents to treat these diseases 3. Theranostics involves the administration of adiagnostic agent: To determine localization in the site or diseasestate under study as a surrogate for a potentialtherapeutic agent with similar chemicalproperties; To examine its biodistribution as predictive of off-target(adverse) effects of the potential therapeuticagent; As an aid in determining the optimal therapeuticdosage or activity to be administered, based onthe anticipated tumoricidal doses measured in thetumor site; To monitor the response to this treatment 4. Also Theranostics is a term that has been used in thecontext of molecular targeting vectors (eg,peptides) labeled either with diagnostic or with therapeuticradionuclides for the diagnosis and therapy of aparticular disease, targeted specifically by thevector at its molecular level 5. Diagram shows example of single-entity theranostic system that combines initial stagingwith imaging (green sunburst as active moiety) followed by therapy with therapeutic versionof imaging (red lightning bolt). 6. Dual purpose radionuclides Emissions suitable for both diagnostic andtherapeutic purposes when molecularly (selectively) targeted usingappropriate carriers, would allow pretherapy low-doseimaging as well as higher-dose therapy inthe same patient 7. Iodine isotopes the first theranostic agent the agent in orally administered seaweed and itsextracts, which had been shown to cure neckswelling due to thyromegaly, was iodine, firstdemonstrated to be a new element in 1813 by SirHumphrey Davy Enrico Fermi produced the first radioiodine, 128I,in 1934 8. 131I First therapeutic application by Hertz and Roberts atMGH for treating thyrotoxicosis (1941) Albert Keston et al (1942) first showed that a childsthyroid cancer could concentrate radioiodine Initial therapeutic efforts were performed without the benefit oftrue imaging until the Cassen and Curtis 21 rectilinear scanner,in 1949 In 1952, Angers first gamma camera, designed for thyroidimaging appeared, enabling visualization of structure/functionas well as for therapy 9. Life Magazine, Oct 1949 Edition 10. 123I Production 11. 123I: advantages More efficient interaction with sodium iodide crystalsthan 131I, with a 159 keV photopeak No beta emission, so the radiation dose to the thyroidgland is a few percent of that from 131I An adequate 13.3-hour half-life allowing commercialshipping More efficient collimation than 131I because of itslower energy A requirement for less expensive shielding 12. Superior images with fewer radiation safetyissues Preference to 123I over 131I for most diagnosticpurposes 13. 124I Once was considered as an unnecessarycontaminant of diagnostic and therapeutic iodineradionuclides Now considered as a potential theranostic agentin management of thyroid cancer 14. 124I cyclotron product124Te[p,n]124I Half life: 4.2days permits functional imaging of many biologicalprocesses employing PET/CT Auger electron emitter high energy of the positrons emitted + presenceof single photons might lead to loss of imagequality due to increased dead time 15. 125I Reactor produced; Applications: protein iodination, RIA kits,brachytherapy (long t1/2) Currently no theranostic applications as it has noobvious benefits over the less expensive 131I 16. Radio-iodinated MIBG worthy agent for both diagnosis and therapy ofendocrine tumors Pheochromocytoma Paraganglioma Carcinoid MTC Neuroblastoma:reduced tumor volumesand lessened excretions ofsymptom-inflictinghormonestumor remission and prolongedsurvival of treated patients 17. 123MALIGNANT PHEOCHROMOCYTOMA:3 SESSIONS OF 131I-MIBG THERAPY 18. Theranostics in NETsApplications in NETs: 68Ga labeled somatostatin analogs(derivatives ofoctreotide, lanreotide) for diagnosis 177Lu and 90Y labeled to identical/similar analog forPRRNTAdvantages of peptide-based targeting: Better pharmacokinetics Minimal/no antigenicity 19. Tumor binding capacity of peptidereceptor radiopharmaceuticals High specific radioactivity preparation In vivo stability of radioligand SSTR expression density in the tumor SSTR subtype expression Efficiency of internalization and recycling Amount of radiopeptide administered 20. Clinical indications of peptidereceptor PET/CT Diagnosis, staging & restaging Detection of unknown primary Therapy stratification Evaluation of therapy response and Prognosis 21. WHO Classification of NETs 22. 90YOwing to higher energy of the beta emissions (935keV), Beneficial in larger tumors Allows irradiaton of tumor cells which are not directlytargeted by the radiopharmaceuticalHowever, Longer range of action, hence high likelihood ofnephrotoxicity 23. 177Lu Emits intermediate energy beta particles (133keV) Beneficial in small sized tumors (tissue range2mm) Concomitant gamma emission property enableseasier imaging with a gamma camera and post-therapydosimetry 24. 64Cu/67Cu64Cu has become of great interest in the last few yearsas a potential PET tracer Short t1/2: 12.7 hr Decays by EC (44) + positron (17) + beta (39)decay modes 25. 64Cu: Nuclear reactions for production 64Ni(p, n)64Cu 68Zn(p, n)64Cu 66Zn(d, )64Cu 26. Why 64Cu??Radionuclide T1/2 BFCA Applications68Ga 1.13 DOTA Diagnosis177Lu 160.8 DOTA Therapy64Cu 12.7 NOTA,TETA,DOTA Diagnosis/Therapy 27. 64Cu: applications64Cu-RGD analogs to monitor changes in tumour vascularity following treatmentwith anti-tumour therapies Potential applications in gliomas, carcinoma breast,carcinoma prostate64Cu-DOTA-trastuzumab Has been used in identifying Her2-positive lesions in casesof primary and metastatic breast cancer 28. Cu-67 with a 2.6-day half-life, is the longest livedradioisotope of CuPhoton energy (keV) Abundance (%)184 48.793 1691 7 Emax = 0.6 MeV (avg = 141 keV) 29. Why Cu-67?? half-life is suitable for imaging slow in-vivopharmacokinetics with agents such as MAbs andother carrier molecules beta particle energy is appropriate for therapy In vitro studies have proven equal effectivenessto 64Cu in inhibiting cell growth and DNAsynthesis 30. ADVANTAGES: 184-keV gamma ray permits imaging of the uptake andbiodistribution of the agent both before and during therapyadministration can also be paired with the positron emitter 64Cu toperform pretherapy biodistribution determinations anddosimetry by PETDRAWBACKS: lack of regular availability of sufficient quantities at a costthat researchers can afford Low specific activity comparable to what is acceptable forantibody therapy 31. Sn-117m one of the best radionuclides for the developmentof theragnostic radiopharmaceuticals, inparticular, for nuclear oncology include palliation of bone pain from osseousmetastases, radiosynovectomy,radioimmunotherapy and cardiovascularapplications 32. In contrast to most other therapeutic betaemitters,117mSn decays via isomeric transition emission of 3 major monoenergetic conversionelectronsEnergies (keV) Abundance (%)127 65129 12152 26 T1/2: 14.0 days 33. very high LET; have short discrete penetrationranges of between 0.22 (127 keV) and 0.29 mm(152 keV) in water effective for therapy of metastatic disease and forcertain other inflammatory conditions (eg,atherosclerotic disease) much reduced myelosuppression and greatlyreduced dose to normal organs 34. Semin Nucl Med 42:151-163 35. 117mSn Beta particlesRange in tissue (m) 290 50-5000Patient shielding forRx/Hospital stay requirementNo/No Yes/Yes 36. 99mTc - MDP 117mSn -DTPA 37. Sn-117m: applications good therapeutic agent for cancer noninvasive molecular imaging and treatment ofactive atheromatous disease (vulnerable plaque,thin-cap fibroatheroma) through use of(i) coronary stents electroplated with 117mSn(ii) 117mSn-labeled specific molecules systemicallytargeted to VP components 38. 18F-FDG as a theranosticagent?? Extensively used in diagnostic positron emissiontomography (PET) in oncology 18F emits energetic positrons with highabundance (96%) and a path length in tissue of0.1-0.2 cm Theoretically, these positrons can kill cancer cellsin the same manner as electrons Additional effects: by-stander/cross-fire 39. 18F-FDG theranosis: smallanimals Meyer et al (Soc Neurosci Abstr 1996;22:948):tumor shrinkage after intratumoral injection ofFDG into glioma xenograft-bearing mice Moadel et al (Breast Cancer Res 2003;5:199-205)(Cancer Res 2005;65:698-702): therapeuticbenefit of FDG in mouse model of breast cancer 40. Breast Cancer Res 2003;5:199-205 41. Caridad et al (Cancer Biother Radiopharm2008;23:371-375): FDG has in vitro as well as invivo cytostatic effects on multiple cancer cell lines(melanoma, colon ca, breast ca) No toxicity upto 6 mCi/20g mouse Dose escalation studies to be performed tovalidate the therapeutic role of FDG 42. Hindrances in using 18F-FDG for Rx High physiologic uptake in brain, skeletal muscles High radiation delivery to the excretory pathway(KUB) 43. To summarize Classical definition of theranostics implies the useof same or similar radiopharmaceuticals formanagement of diseases However, the definition and the scope oftheranostics has broadened to involve variousnovel, innovative and safer techniques 44. However, an increased and reliable availability atreasonable cost of the theranostic radionuclides hasremained a major issue,must be addressed before we successfully put intoroutine clinical practice.It is worth emphasizing that the various nuclearmedicine modalities optimally fulfil the requirementsto convenitently carry out the practices ofpersonalized medicineThis field is an exciting development that marks thefuture of the field of nuclear medicine 45. THANK YOU