[{"id":"alpha-therapy-roadmap","kind":"roadmap","name":"Alpha-emitter roadmap: radium-223 → 225Ac-PSMA-617 → a phase 3 pipeline","aka":[],"tldr":"Alpha particles carry much more energy over a much shorter distance than the beta particles used in Lutathera and Pluvicto, so they can be more powerful against small clusters of cancer cells. The first alpha drug was approved in 2013; a wave of alpha versions of existing beta drugs is now in late-stage testing, and the isotopes are still scarce.","summary":"Alpha-particle therapy began clinically with radium-223 dichloride, approved by the FDA on 15 May 2013 for bone metastases in prostate cancer after the ALSYMPCA trial, though radium-223 is a bone-seeker rather than a targeted radioligand. The targeted-alpha era proper starts with Kratochwil and colleagues at Heidelberg and the Joint Research Centre Karlsruhe, who treated the first patients with 225Ac-PSMA-617 in 2014 and reported complete responses in two heavily pretreated men with metastatic castration-resistant prostate cancer in 2016, followed by empirical dose-finding in a larger series in 2017.\n\nThat compassionate-use experience seeded a pipeline of sponsor-run trials repeating the beta-to-alpha substitution across targets: 225Ac-DOTATATE (RYZ101, RayzeBio/BMS) in the ACTION-1 trial for neuroendocrine tumours progressing after 177Lu-DOTATATE; 225Ac-PSMA-I&T (FPI-2265, Fusion Pharmaceuticals/AstraZeneca) in AlphaBreak for prostate cancer after 177Lu-PSMA; 225Ac-PSMA-617 (AAA817, Novartis) in a phase 3 programme; and 212Pb-DOTAMTATE (AlphaMedix, RadioMedix/Orano Med/Sanofi), whose phase 2 ALPHAMEDIX-02 study reported that it met all primary efficacy endpoints in October 2025. Every one of these programmes is capacity-constrained: actinium-225 in particular is scarce, and lead-212 and actinium-225 production are both being scaled by companies such as TerraPower Isotopes and Orano Med.\n\nThe unresolved questions are whether alpha activity will translate into a survival benefit large enough for approval once the phase 3 readouts arrive (2026-2028 on current registry estimates), whether the added myelotoxicity and xerostomia seen in compassionate-use series are tolerable at scale, and whether supply can grow fast enough to support first-line or earlier-line use rather than remaining a last-resort option after beta radioligand therapy fails.","asOf":"2026-09-22","links":[{"label":"FDA: Alsympca (radium-223 dichloride) approval, May 2013","url":"https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203971Orig1s000TOC.cfm"},{"label":"Kratochwil et al., 225Ac-PSMA-617 for PSMA-targeted alpha-radiation therapy (J Nucl Med 2016)","url":"https://pubmed.ncbi.nlm.nih.gov/27390158/"},{"label":"RayzeBio/ClinicalTrials.gov: ACTION-1 (NCT05477576)","url":"https://clinicaltrials.gov/study/NCT05477576"},{"label":"Sanofi: AlphaMedix (212Pb-DOTAMTATE) ALPHAMEDIX-02 phase 2 results, October 2025","url":"https://www.sanofi.com/en/media-room/press-releases/2025/2025-10-08-05-00-00-3163053"},{"label":"TerraPower Isotopes: Bellwether Laboratory groundbreaking, May 2026","url":"https://www.terrapower.com/TerraPower-Isotopes-Breaks-Ground-on-Worlds-Largest-Actinium-225-Manufacturing-Facility-in-Philadelphia"}],"tags":[],"related":["lu-177","ac-225","ra-223","pb-212"],"indications":[],"sections":[],"technologies":["targeted-alpha-therapy","actinium-225-supply","radioligand-therapy","prrt"],"targets":[],"drugs":["radium-223","ryz101","fpi-2265","ac225-psma","alphamedix"],"companies":["rayzebio","fusion-pharma","novartis","orano-med","radiomedix","terrapower-isotopes"],"institutions":[],"pathways":[],"terms":[],"trials":["alsympca","action-1","alphabreak","alphamedix-02"],"people":["clemens-kratochwil","uwe-haberkorn"],"bottlenecks":[],"keyPapers":["paper-alsympca-radium-223-nejm-2013"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"2013","title":"Radium-223: the first alpha emitter approved","description":"The FDA approves radium-223 dichloride on 15 May 2013 for symptomatic bone metastases in castration-resistant prostate cancer, based on the ALSYMPCA trial (median overall survival 14.9 vs 11.3 months). Radium-223 is a bone-seeking calcium mimetic rather than a receptor-targeted ligand, but it establishes that an alpha emitter can be given systemically and safely.","refs":["radium-223","alsympca","paper-alsympca-radium-223-nejm-2013"],"status":"historic"},{"era":"2014-2017","title":"First-in-human targeted alpha therapy: 225Ac-PSMA-617","description":"Clinical investigation of 225Ac-PSMA-617 begins in 2014 at Heidelberg University Hospital with the Joint Research Centre Karlsruhe. Kratochwil et al. report complete biochemical and imaging responses in two heavily pretreated men with mCRPC in 2016 (J Nucl Med), then empirical dose-finding (100 kBq/kg every 8 weeks) in a larger series in 2017, establishing the first targeted-alpha treatment protocol in humans.","refs":["clemens-kratochwil","uwe-haberkorn"],"status":"historic"},{"era":"2018-2023","title":"Sponsor-run alpha programmes multiply","description":"Compassionate-use experience is followed by company-sponsored trials repeating the beta-to-alpha substitution across targets and companies: RYZ101 (225Ac-DOTATATE) enters ACTION-1 for GEP-NETs progressing after 177Lu-SSA therapy; FPI-2265 (225Ac-PSMA-I&T) enters AlphaBreak for mCRPC after 177Lu-PSMA; Novartis begins a phase 3 programme for AAA817 (225Ac-PSMA-617); and RadioMedix/Orano Med complete enrolment of the phase 2 ALPHAMEDIX-02 trial of 212Pb-DOTAMTATE in 2023.","refs":["action-1","alphabreak","alphamedix-02","rayzebio","fusion-pharma","novartis","orano-med","radiomedix"],"status":"historic"},{"era":"2024-2026","title":"Supply scales and the first phase 2 readouts land","description":"TerraPower Isotopes announces it is producing actinium-225 at commercial scale via weekly production runs from October 2024. 212Pb-DOTAMTATE receives FDA Breakthrough Therapy designation in 2024, and the ALPHAMEDIX-02 phase 2 study reports in October 2025 that it met all primary efficacy endpoints (ORR 60% in PRRT-naive patients), the first positive alpha-PRRT phase 2 readout in neuroendocrine tumours.","refs":["terrapower-isotopes","alphamedix-02","orano-med"],"status":"current"},{"era":"2026-2029","title":"Phase 3 readouts and a step-change in actinium-225 capacity","description":"ACTION-1, AlphaBreak and the AAA817 phase 3 programme are all due to reach their primary completion dates between late 2026 and 2028, which will determine whether alpha radioligands can be filed for approval as a post-beta salvage option. TerraPower Isotopes breaks ground on a $450m Philadelphia facility in May 2026 intended to increase global actinium-225 production capacity twentyfold.","refs":["action-1","alphabreak","novartis","terrapower-isotopes"],"status":"emerging"},{"era":"2029+","title":"Speculative: alpha therapy in earlier lines","description":"If phase 3 trials read out positively and actinium-225 and lead-212 supply scales as planned, alpha radioligands could move from post-beta salvage into earlier lines, including hormone-sensitive prostate cancer, and combine with PARP inhibitors or immunotherapy. This depends on both an approval and a resolved supply chain; neither is confirmed as of this record's `asOf` date.","refs":["targeted-alpha-therapy","idea-alpha-first-mhspc","idea-alpha-after-adc"],"status":"speculative"}],"watch":[{"item":"ACTION-1 (RYZ101, RayzeBio/BMS) phase 3 primary completion","expected":"Primary Completion (Estimated): 2026-12","source":"https://clinicaltrials.gov/study/NCT05477576","refs":["action-1","rayzebio"]},{"item":"AlphaBreak (FPI-2265, Fusion Pharmaceuticals) phase 2 primary completion","expected":"Estimated Completion: July 23, 2026","source":"https://www.ancora.ai/en/detailsradiopharm/NCT06402331","refs":["alphabreak","fusion-pharma"]},{"item":"AAA817 (Novartis, PSMAcTION, NCT06780670) phase 3 primary completion","expected":"Primary completion date: Jun 27, 2028 (Anticipated)","source":"https://www.allclinicaltrials.com/study/NCT06780670","refs":["novartis"]},{"item":"TerraPower Isotopes' Philadelphia cGMP actinium-225 facility begins production","expected":"Production of cGMP actinium-225 beginning in 2029","source":"https://www.terrapower.com/TerraPower-Isotopes-announces-cGMP-manufacturing-facility","refs":["terrapower-isotopes"]}]},{"id":"dosimetry-roadmap","kind":"roadmap","name":"Dosimetry roadmap: MIRD schema → fixed dosing → personalised, image-based dose","aka":[],"tldr":"Working out how much radiation a treatment actually delivers to a tumour and to healthy organs, rather than just giving everyone the same fixed amount, could let doctors treat some patients more and some less. The tools to do this patient by patient exist and are used in some specialist centres, but most approved radioligand therapies are still given at one fixed dose to everyone.","summary":"Internal radiation dosimetry has a formal history: the Society of Nuclear Medicine's Medical Internal Radiation Dose (MIRD) Committee was formed in 1965, and its 1968 MIRD Pamphlet No. 1 (Loevinger and Berman) introduced the absorbed-fraction and S-value formalism that still underlies software such as OLINDA. For decades this framework was applied mainly to diagnostic radiopharmaceutical dose estimates rather than to individualising therapy.\n\nPersonalised, image-based dosimetry for peptide receptor radionuclide therapy (PRRT) was developed and tested prospectively from the early 2010s, principally by Swedish groups: Sandström et al. and Garske-Román et al. at Uppsala, and Sundlöv et al. at Lund, used SPECT/CT-based kidney dosimetry to vary the number of 177Lu-DOTATATE cycles per patient up to a fixed renal biologically effective dose (27 Gy, with a 40 Gy option in low-risk patients) rather than a fixed four-cycle course. Despite this evidence base, the pivotal trials that led to approval, NETTER-1 for Lutathera (FDA, January 2018) and VISION for Pluvicto (FDA, March 2022), used fixed activities and a fixed number of cycles, and the resulting labels do not require patient-specific dosimetry for in-label use.\n\nThe current step is guideline consolidation: the joint EANM/SNMMI procedure guideline for 177Lu-PSMA radioligand therapy (2023) states plainly that fixed dosing was how the drug was approved and that dosimetry is not mandatory in-label, while EANM's 2022 dosimetry-committee recommendations and its 2024 guidance for first-in-human studies push in the opposite direction, calling for patient-specific absorbed-dose calculation as standard practice, especially early in a new drug's development. The emerging and speculative steps are quantitative SPECT/CT and total-body PET made fast and automated enough for routine clinical dosimetry, and trials that prospectively randomise dosimetry-guided dosing against the fixed-activity standard of care.","asOf":"2026-09-22","links":[{"label":"From the MIRD Committee: history and founding, 1965 (J Nucl Med)","url":"https://jnm.snmjournals.org/content/jnumed/50/2/25N.full.pdf"},{"label":"Sundlöv et al., individualised 177Lu-DOTATATE treatment based on kidney dosimetry (Eur J Nucl Med Mol Imaging 2017)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5506097/"},{"label":"Joint EANM/SNMMI procedure guideline for 177Lu-PSMA-RLT (2023)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10317889/"}],"tags":[],"related":["lu-177"],"indications":[],"sections":[],"technologies":["radioligand-dosimetry","in-vivo-dosimetry","spect-ct","total-body-pet-screening"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["dosimetry","gray-unit"],"trials":["netter-1","vision"],"people":["clemens-kratochwil","ken-herrmann"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1965-1968","title":"The MIRD schema","description":"The Society of Nuclear Medicine forms the Medical Internal Radiation Dose (MIRD) Committee in 1965. Its 1968 MIRD Pamphlet No. 1 (Loevinger and Berman) introduces the absorbed-fraction and S-value formalism for internal dosimetry, replacing older exposure-based (roentgen) methods and forming the basis of modern dosimetry software.","refs":["dosimetry"],"status":"historic"},{"era":"2012-2017","title":"Prospective personalised PRRT dosimetry trials","description":"Swedish groups develop and prospectively test image-based, patient-specific PRRT dosing: Sandström and Garske-Román's Uppsala cohort of 200 patients caps 177Lu-DOTATATE at a 23 Gy renal dose rather than a fixed cycle count, and Sundlöv's Lund phase 2 trial (NCT01456078) individualises cycles up to a 27 Gy renal biologically effective dose, reporting the approach as feasible and safe.","refs":["prrt","sstr2","idea-net-dosimetry-prrt"],"status":"historic"},{"era":"2018-2022","title":"Fixed-activity dosing wins regulatory approval","description":"Despite the personalised-dosimetry evidence base, the pivotal trials that gained approval both use fixed dosing: NETTER-1 (Lutathera, FDA January 2018) gives 7.4 GBq every 8 weeks for 4 doses, and VISION (Pluvicto, FDA March 2022) gives 7.4 GBq every 6 weeks for up to 6 doses, with dosimetry collected in a VISION sub-study of only 29 patients rather than used to set the dose.","refs":["netter-1","vision","lutathera","pluvicto"],"status":"historic"},{"era":"2022-2024","title":"Guidelines diverge on whether dosimetry should be mandatory","description":"EANM's dosimetry committee publishes recommendations for 177Lu-labelled somatostatin-receptor- and PSMA-targeting ligands (2022). The joint EANM/SNMMI procedure guideline for 177Lu-PSMA radioligand therapy (2023) states that '[177Lu]Lu-PSMA-617 was approved using fixed standard treatment activities, and patient individual dosimetry is not mandatory for in-label use', while acknowledging significant inter-patient variability. EANM's 2024 guidance document for first-in-human studies and early-phase trials calls for patient-specific absorbed-dose calculation as standard in that earlier setting.","refs":["radioligand-dosimetry","in-vivo-dosimetry"],"status":"current"},{"era":"2024-2028","title":"Emerging: faster quantitative imaging for routine dosimetry","description":"Work continues on shortening and simplifying SPECT/CT-based kidney and bone-marrow dosimetry protocols (for example, reducing the number of post-therapy imaging time points needed) and on total-body PET platforms whose sensitivity could make same-day, whole-body quantitative dosimetry practical outside specialist academic centres.","refs":["spect-ct","total-body-pet-screening","idea-total-body-pet-dosimetry"],"status":"emerging"},{"era":"2028+","title":"Speculative: dosimetry-personalised dosing as standard of care","description":"If ongoing and future randomised trials show that dosimetry-guided cycle number or activity improves outcomes or reduces toxicity compared with fixed dosing, regulators could require or incentivise individualised dosing for new and existing radioligand therapies rather than leaving it as an optional academic practice.","refs":["idea-net-dosimetry-prrt"],"status":"speculative"}],"watch":[{"item":"Joint EANM/SNMMI procedure guideline for 177Lu-PSMA-RLT, next revision","source":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10317889/","refs":["radioligand-dosimetry"]}]},{"id":"isotope-supply-roadmap","kind":"roadmap","name":"Isotope supply roadmap: reactor dependence → non-uranium production → accelerator-made actinium","aka":[],"tldr":"The radioactive ingredients that make theranostics work come from a small number of ageing nuclear reactors, generators and accelerators around the world. A shortage anywhere in that chain delays cancer scans and treatments; new non-uranium and accelerator-based production lines are being built to fix that, but they take years and hundreds of millions of dollars.","summary":"For decades the world's molybdenum-99 (the parent of technetium-99m, the workhorse of conventional nuclear medicine) came almost entirely from a handful of ageing research reactors using highly enriched uranium targets, concentrated in Canada, the Netherlands, Belgium, France and South Africa. When Canada's NRU reactor and the Netherlands' HFR both went offline for repairs in 2009-2010, the resulting shortage disrupted nuclear medicine services worldwide and triggered a policy response.\n\nThe US response, formalised in the American Medical Isotope Production Act of 2012, funded non-uranium domestic production. NorthStar Medical Radioisotopes' RadioGenix System, producing molybdenum-99 without highly enriched uranium via neutron capture at the University of Missouri Research Reactor, received FDA approval in February 2018, the first domestic Mo-99 production in roughly three decades. Lutetium-177 demand then rose sharply once Lutathera (2018) and Pluvicto (2022) were approved, straining the same reactor capacity and the enriched ytterbium-176 supply used for no-carrier-added production.\n\nThe newest constraint is actinium-225 for targeted alpha therapy, historically harvested in gram quantities from thorium-229 stockpiles. TerraPower Isotopes announced commercial-scale, weekly actinium-225 production in October 2024 using a natural decay method from thorium-229 recovered from US Department of Energy uranium-233 stocks, and in 2026 broke ground on a $450 million Philadelphia facility intended to increase global capacity twentyfold, with production expected from 2029. Whether reactor, cyclotron and accelerator capacity can keep pace with a growing radioligand pipeline, without a repeat of the 2009-2010 shortage, is the open question this roadmap tracks.","asOf":"2026-09-22","links":[{"label":"DOE/NNSA: FDA approval of domestically-produced, non-uranium based Mo-99, February 2018","url":"https://www.energy.gov/articles/doennsa-partnership-us-healthcare-industry-results-fda-approval-domestically-produced-non"},{"label":"TerraPower Isotopes: reaches market-scale production of actinium-225, October 2024","url":"https://www.terrapower.com/tpi-brings-actinium-225-to-market"},{"label":"TerraPower Isotopes: Bellwether Laboratory groundbreaking, May 2026","url":"https://www.terrapower.com/TerraPower-Isotopes-Breaks-Ground-on-Worlds-Largest-Actinium-225-Manufacturing-Facility-in-Philadelphia"},{"label":"NorthStar: FDA approves additional Mo-99 filling lines, February 2020","url":"https://www.itnonline.com/content/fda-approves-additional-molybdenum-99-mo-99-filling-lines-northstar-medical-radioisotopes"}],"tags":[],"related":["tc-99m","mo-99","lu-177","ac-225"],"indications":[],"sections":[],"technologies":["research-reactor-isotope-production","therapy-isotope-supply-chain","actinium-225-supply","cyclotron-isotope-production","radiopharmacy-network"],"targets":[],"drugs":[],"companies":["northstar-medical-radioisotopes","shine-technologies","terrapower-isotopes","orano-med","nordion","ire","ntp-radioisotopes","ansto","nusano"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1960s-2008","title":"Reactor-dependent, HEU-based supply","description":"Global molybdenum-99 supply concentrates in a small number of ageing, mostly HEU-fuelled research reactors (Canada's NRU, the Netherlands' HFR, Belgium's BR2, France's OSIRIS, South Africa's SAFARI-1), each serving large multi-country markets with no domestic US production.","refs":["research-reactor-isotope-production"],"status":"historic"},{"era":"2009-2010","title":"The global Mo-99 shortage","description":"NRU (Chalk River) and HFR both go offline for unplanned repairs at overlapping times, causing a worldwide shortage of molybdenum-99/technetium-99m that disrupts nuclear medicine imaging and prompts a US and international policy response to diversify supply.","refs":["research-reactor-isotope-production"],"status":"historic"},{"era":"2012-2018","title":"Non-HEU domestic Mo-99 production","description":"The American Medical Isotope Production Act (2012) directs the US Department of Energy/NNSA to fund non-HEU Mo-99 production. NorthStar Medical Radioisotopes' RadioGenix System, using neutron-capture production of Mo-99 at the University of Missouri Research Reactor, receives FDA approval on 8 February 2018, the first domestic, non-uranium Mo-99 production since the 1980s.","refs":["northstar-medical-radioisotopes"],"status":"historic"},{"era":"2018-2024","title":"Lutetium-177 demand outpaces capacity","description":"Approvals of Lutathera (2018) and Pluvicto (2022) sharply increase demand for reactor-produced lutetium-177, straining both irradiation capacity and the enriched ytterbium-176 supply used for no-carrier-added Lu-177 production; multiple national reactor operators (ANSTO, IRE, NTP Radioisotopes) expand production lines.","refs":["therapy-isotope-supply-chain","pluvicto","lutathera"],"status":"current"},{"era":"2024-2026","title":"Accelerator-made actinium-225 reaches commercial scale","description":"TerraPower Isotopes announces commercial-scale, weekly actinium-225 production from October 2024, using a natural decay method from thorium-229 recovered from US Department of Energy uranium-233 stockpiles in partnership with Isotek. In March 2026 the company announces a second, much larger facility in Philadelphia.","refs":["terrapower-isotopes","actinium-225-supply"],"status":"current"},{"era":"2026-2029","title":"Building twentyfold actinium-225 capacity","description":"TerraPower Isotopes breaks ground on its $450m Bellwether Laboratory in Philadelphia in May 2026, intended to increase global actinium-225 production capacity twentyfold alongside expansion at its Everett, Washington site; the Pennsylvania state government contributes grant funding. Production is expected to begin in 2029.","refs":["terrapower-isotopes"],"status":"emerging"},{"era":"2029+","title":"Speculative: a resilient, diversified isotope supply","description":"Proposals under discussion include Western enrichment of ytterbium-176 to add a second Lu-177 supplier, a coordinated international reserve and shared schedule for medical isotope reactors, regional radiopharmacy hubs with harmonised transport rules for short-lived isotopes, and a global isotope supply observatory that forecasts shortages before they happen.","refs":["idea-reg-yb176-enrichment-capacity","idea-reg-medical-isotope-reactor-reserve","idea-reg-regional-radiopharmacy-hubs","idea-reg-isotope-supply-observatory","idea-reg-legacy-radium-recovery-ac225"],"status":"speculative"}],"watch":[{"item":"NorthStar RadioGenix expansion and additional Mo-99 filling lines","expected":"FDA approval of two additional Mo-99 filling lines, announced 18 February 2020","source":"https://www.itnonline.com/content/fda-approves-additional-molybdenum-99-mo-99-filling-lines-northstar-medical-radioisotopes","refs":["northstar-medical-radioisotopes"]},{"item":"TerraPower Isotopes' Philadelphia cGMP actinium-225 facility begins production","expected":"Production of cGMP actinium-225 beginning in 2029","source":"https://www.terrapower.com/TerraPower-Isotopes-announces-cGMP-manufacturing-facility","refs":["terrapower-isotopes"]}]},{"id":"molecular-imaging-roadmap","kind":"roadmap","name":"Molecular imaging roadmap: FDG → PSMA → FAP → antigen and immune PET","aka":[],"tldr":"From a sugar tracer that lights up most cancers to tracers that show a single protein, a stromal cell type, or the immune cells inside a tumour.","summary":"The molecular imaging roadmap moves from PET scanners and FDG, made routine by PET/CT, to receptor tracers such as 68Ga-DOTATATE and PSMA PET that outperform anatomic imaging and enable theranostics. The current step adds stromal FAPI PET and total-body scanners, and the emerging step brings drug-target and immune PET: TROP2, HER2, B7-H3 and Nectin-4 tracers to select and sequence ADCs, CD8 and granzyme PET to monitor immunotherapy, and PARP PET. The speculative end is multi-tracer same-day imaging, PET-guided adaptive radiotherapy and imaging-derived digital twins. Each new tracer converts a biopsy biomarker into a whole-body map; the route sits in the Imaging section and links PET, PET/CT, FDG PET, PSMA PET, FAPI PET, TROP2 PET, HER2 PET, immuno-PET, PARP PET and PET/MRI.","asOf":"2026-09-04","links":[{"label":"VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2107322"},{"label":"DETECT-A: a blood test plus PET-CT found treatable cancers in 10,000 women with no symptoms (Science 2020)","url":"https://doi.org/10.1126/science.abb9601"}],"tags":[],"related":["ga-68"],"indications":[],"sections":[],"technologies":["pet","pet-ct","fdg-pet","psma-pet","fapi-pet","trop2-pet","her2-pet","immuno-pet","parp-pet","pet-mri"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1975-2001","title":"PET and FDG","description":"PET scanners (1975) and FDG (1976) developed; FDG PET adopted for lymphoma, lung, melanoma staging in the 1990s; PET/CT (2001) makes it routine.","refs":["fdg-pet","pet-ct"],"status":"historic"},{"era":"2008-2020","title":"Receptor PET: SSTR and PSMA","description":"68Ga-DOTATATE (Netspot 2016) and 68Ga/18F-PSMA (2020-21) show receptor tracers outperform anatomic imaging and enable theranostics.","refs":["psma-pet","sstr2"],"status":"historic"},{"era":"2018-2026","title":"Stromal PET and total-body scanners","description":"FAPI tracers image >90% of epithelial cancers with high contrast; registrational trials underway. Total-body PET (uEXPLORER, Quadra) enables 40x sensitivity, low-dose paediatric and dynamic imaging. 18F-FES (ER) approved 2020; 89Zr-girentuximab (CAIX) filed. Pylarify TruVu approved 2026.","refs":["fapi-pet","pet-ct","united-imaging","pylarify"],"status":"current"},{"era":"2024-2028","title":"Drug-target and immune PET","description":"TROP2, HER2, B7-H3, Nectin-4 antibody and nanobody tracers to select and sequence ADCs; CD8 and granzyme PET to predict and monitor immunotherapy response; PARP PET for PARP-inhibitor selection; AI quantification and radiomics on standard scans.","refs":["trop2-pet","her2-pet","immuno-pet","parp-pet"],"status":"emerging"},{"era":"2028+","title":"Speculative","description":"Multi-tracer same-day imaging on total-body PET; PET-guided adaptive radiotherapy (biology-guided RT); routine antigen PET before every ADC; imaging-derived digital twins of tumour heterogeneity feeding treatment algorithms.","refs":[],"status":"speculative"}],"watch":[]},{"id":"neuro-imaging-roadmap","kind":"roadmap","name":"Neuro-oncology imaging roadmap: FDG PET → amino acid PET → SSTR2 theranostics in meningioma","aka":[],"tldr":"Ordinary sugar-based PET scans do not work well in the brain because healthy brain tissue itself uses a lot of sugar. Nuclear medicine had to develop tracers that light up brain tumours specifically, first amino acid tracers for gliomas and then a receptor tracer that also opens the door to a matched radioactive treatment for meningioma.","summary":"FDG PET has a structural limitation in the brain: normal grey matter has high baseline glucose uptake, so FDG contrast between tumour and healthy brain tissue is poor, unlike its performance in most body cancers. This drove development from the 1980s onward of radiolabelled amino acid tracers, principally 11C-methionine and later 18F-FET, which exploit the increased amino acid transport of tumour cells against a low physiological background in normal brain.\n\nThese tracers were gradually adopted into formal guidance: the PET-RANO working group and EANO published evidence-based recommendations for PET imaging in gliomas in 2016, followed by the joint EANM/EANO/RANO/SNMMI practice guideline (version 1.0) for glioma PET imaging with radiolabelled amino acids and FDG, published in 2019, standardising acquisition and interpretation (for example, a tumour-to-brain ratio threshold of 1.6-1.8 for 18F-FET). An updated RANO/EANO policy review in 2025 strengthened several of these recommendations, including for delineating tumour extent and distinguishing recurrence from treatment-related change.\n\nA parallel and largely separate strand targets meningioma, a tumour that (unlike most gliomas) reliably overexpresses somatostatin receptor 2 (SSTR2). Rachinger et al. (2015) showed that 68Ga-DOTATATE PET uptake correlates with SSTR2 expression and outperforms MRI sensitivity (90% vs 79%) for discriminating meningioma from tumour-free tissue, and it is now used for surgical and radiotherapy planning, particularly at the skull base. Because meningioma expresses the same target as neuroendocrine tumours, it has become a candidate for the same theranostic pairing: a phase 1/2 trial of the alpha emitter 225Ac-DOTATATE (RYZ101) in progressive or recurrent intracranial meningioma opened at Ohio State, testing whether the SSTR theranostic model developed for neuroendocrine tumours extends into neuro-oncology.","asOf":"2026-09-22","links":[{"label":"Rachinger et al., increased 68Ga-DOTATATE uptake discriminates meningioma and tumour-free tissue (J Nucl Med 2015)","url":"https://pubmed.ncbi.nlm.nih.gov/25635133/"},{"label":"Joint EANM/EANO/RANO practice guidelines/SNMMI procedure standards for glioma PET, version 1.0 (2019)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC6351513/"},{"label":"Update to the RANO working group and EANO recommendations for PET imaging in gliomas (Lancet Oncology 2025)","url":"https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(25)00193-7/fulltext"},{"label":"ClinicalTrials.gov: RYZ101 for progressive/recurrent intracranial meningioma (NCT07150806)","url":"https://clinicaltrials.gov/study/NCT07150806"}],"tags":[],"related":["f-18","ga-68","c-11","ac-225"],"indications":["glioblastoma","meningioma"],"sections":[],"technologies":["pet","pet-ct","fdg-pet","sstr-pet","astatine-211-alpha-therapy"],"targets":["sstr2"],"drugs":["fludeoxyglucose-f18","ga68-dotatate","ryz101"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1980s-1990s","title":"FDG's limits in the brain drive amino acid PET","description":"FDG PET is limited in neuro-oncology by high physiological glucose uptake in normal grey matter, which reduces tumour-to-background contrast. This drives clinical development of radiolabelled amino acid tracers, principally 11C-methionine, which show much better contrast against normal brain from the 1980s onward.","refs":["fdg-pet","glioblastoma"],"status":"historic"},{"era":"2000s-2016","title":"18F-FET and the first evidence-based PET guidance for glioma","description":"O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET), an 18F-labelled amino acid tracer with a longer half-life than 11C-methionine, is adopted widely in Europe through the 2000s and 2010s. The PET-RANO working group and EANO publish the first evidence-based recommendations for the clinical use of PET imaging in gliomas in Neuro-Oncology in 2016.","refs":["glioblastoma"],"status":"historic"},{"era":"2015","title":"68Ga-DOTATATE PET for meningioma","description":"Rachinger et al. show, using spatially precise neuronavigated tissue sampling during surgery, that 68Ga-DOTATATE PET uptake correlates with SSTR2 expression and detects meningioma tissue with higher sensitivity than MRI (90% vs 79%), establishing SSTR2 PET as a tool for meningioma delineation, particularly in the skull base and after treatment.","refs":["meningioma","sstr2","ga68-dotatate"],"status":"historic"},{"era":"2019-2025","title":"Joint practice guidelines standardise glioma PET","description":"The joint EANM/EANO/RANO/SNMMI practice guideline (version 1.0) for imaging gliomas with PET using radiolabelled amino acids and FDG is published in 2019, standardising acquisition protocols and uptake thresholds (for example, an 18F-FET tumour-to-brain ratio of 1.6-1.8). An updated RANO/EANO policy review in 2025 strengthens the recommendation level for several uses, including delineating glioma extent and distinguishing recurrence from treatment-related change.","refs":["glioblastoma"],"status":"current"},{"era":"2020-2026","title":"68Ga-DOTATATE PET in routine meningioma management","description":"SSTR2 PET with 68Ga-DOTATATE or DOTATOC becomes an established adjunct to MRI for meningioma treatment planning, particularly for delineating disease extent at the skull base, detecting bony invasion, and distinguishing residual tumour from post-surgical or post-radiation change.","refs":["meningioma","sstr2"],"status":"current"},{"era":"2025-2028","title":"Emerging: SSTR2 theranostics extends into meningioma therapy","description":"A phase 1/2 trial of the alpha emitter 225Ac-DOTATATE (RYZ101) for progressive or recurrent intracranial meningioma (WHO grades 1-3) opens at Ohio State, using 68Ga-DOTATATE PET to select and follow patients, testing whether the diagnostic-therapeutic SSTR2 pairing developed for neuroendocrine tumours can extend into a tumour type managed mainly by surgery and radiotherapy.","refs":["meningioma"],"status":"emerging"},{"era":"2028+","title":"Speculative: broader receptor and alpha-emitter use in brain tumours","description":"If SSTR2 theranostics in meningioma shows benefit, other brain and skull-base tumours with a defined receptor target could follow the same diagnostic-therapeutic pairing, and locoregional alpha-emitter delivery (for example convection-enhanced delivery of astatine-211 conjugates, under early investigation for glioma) could extend targeted radiotherapy to tumours where systemic dosing is limited by the blood-brain barrier.","refs":["astatine-211-alpha-therapy"],"status":"speculative"}],"watch":[{"item":"RYZ101 for progressive/recurrent intracranial meningioma, Ohio State trial","source":"https://clinicaltrials.gov/study/NCT07150806","refs":["meningioma"]}]},{"id":"psma-theranostics-roadmap","kind":"roadmap","name":"PSMA theranostics roadmap: antigen discovery → PSMA PET → 177Lu-PSMA-617 → earlier lines and alpha","aka":[],"tldr":"Prostate-specific membrane antigen was found on prostate cancer cells in 1987. It took until 2020-2022 for scans and treatments that target it to reach approval, but once they did, PSMA PET and Pluvicto changed how metastatic prostate cancer is staged and treated, and the same target is now being tried earlier in the disease and with more powerful alpha particles.","summary":"Prostate-specific membrane antigen (PSMA) was first identified in 1987 when Horoszewicz and Murphy raised the monoclonal antibody 7E11-C5 against the LNCaP prostate cancer cell line; Heston and Fair's group at Memorial Sloan Kettering cloned the PSMA gene in 1993. The first PSMA-targeted imaging agent to reach approval, indium-111 capromab pendetide (ProstaScint), was approved by the FDA on 28 October 1996, but bound only an intracellular epitope and had limited clinical impact.\n\nThe modern era begins with small-molecule PSMA ligands: Eder and colleagues at the German Cancer Research Center (DKFZ) Heidelberg synthesised the gallium-68-labelled HBED-CC compound that became PSMA-11 in 2012, building on first-in-human work from 2011. It took until 1 December 2020 for the FDA to approve 68Ga-PSMA-11 (jointly, as separate applications from UCSF and UCLA), the first PSMA PET agent approved in the US, followed by the first commercially distributable PSMA PET agent, Pylarify (piflufolastat F 18), on 26 May 2021. On the therapy side, Kratochwil's Heidelberg group had already shown in 2016 that the corresponding alpha-emitting ligand, 225Ac-PSMA-617, could produce complete responses; the beta-emitting version, 177Lu-PSMA-617 (Pluvicto), was approved by the FDA on 23 March 2022 for post-chemotherapy mCRPC, based on the VISION trial (a 38% reduction in risk of death).\n\nThe label then moved earlier: on 28 March 2025 the FDA expanded Pluvicto's indication, based on the PSMAfore trial, to PSMA-positive mCRPC patients who have progressed on one androgen receptor pathway inhibitor and are considered appropriate to delay chemotherapy, removing the prior-taxane requirement and roughly tripling the eligible US population. The alpha-emitting analogue of Pluvicto, 225Ac-PSMA-617 (AAA817, Novartis), and a second alpha PSMA ligand, FPI-2265 (225Ac-PSMA-I&T, Fusion Pharmaceuticals), are both now in phase 3 programmes for patients whose disease has progressed on 177Lu-PSMA, the next planned step in the sequence.","asOf":"2026-09-22","links":[{"label":"FDA: Ga 68 PSMA-11 injection approval (UCSF/UCLA), December 2020","url":"https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212643Orig1s000Approv.pdf"},{"label":"Lantheus: FDA approval of Pylarify, May 2021","url":"https://investor.lantheus.com/news-releases/news-release-details/lantheus-receives-us-fda-approval-pylarifyr-piflufolastat-f-18"},{"label":"FDA: Pluvicto (lutetium Lu 177 vipivotide tetraxetan) approval summary, March 2022 (PMC)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10159870/"},{"label":"FDA: Pluvicto label expansion based on PSMAfore, March 2025","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication"}],"tags":[],"related":["f-18","ga-68","in-111","lu-177","ac-225"],"indications":["prostate","prostate-mcrpc"],"sections":[],"technologies":["psma-pet","lu177-radioligand-therapy","targeted-alpha-therapy"],"targets":["psma"],"drugs":["ga68-psma-11","pylarify","pluvicto","illuccix","locametz","lu177-psma-it","ac225-psma"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["vision","psmafore","alphabreak"],"people":["clemens-kratochwil","uwe-haberkorn","michael-morris","thomas-hope","hofman-michael"],"bottlenecks":[],"keyPapers":["paper-vision-nejm-2021","paper-propsma-hofman-lancet-2020"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1987-1996","title":"PSMA discovered; first imaging agent approved","description":"Horoszewicz, Kawinski and Murphy raise the 7E11-C5 monoclonal antibody against PSMA in 1987; Heston and Fair's group at Memorial Sloan Kettering clone the PSMA gene in 1993. The FDA approves the first PSMA-targeted imaging agent, indium-111 capromab pendetide (ProstaScint, Cytogen), on 28 October 1996, though the antibody binds an intracellular epitope and offers limited sensitivity.","refs":["prostate"],"status":"historic"},{"era":"2011-2012","title":"Small-molecule PSMA ligands and first-in-human PET","description":"The Heidelberg group at the German Cancer Research Center (DKFZ) reports first-in-human imaging with a gallium-68-labelled small-molecule PSMA inhibitor in 2011; Eder and colleagues publish the synthesis of the HBED-CC-chelated compound that becomes PSMA-11 in 2012, replacing antibody-based imaging with fast, high-contrast small-molecule PET.","refs":["psma-pet","uwe-haberkorn"],"status":"historic"},{"era":"2016","title":"225Ac-PSMA-617: alpha therapy proof of concept","description":"Kratochwil, Bruchertseifer and colleagues report complete biochemical and imaging responses with 225Ac-PSMA-617 in two heavily pretreated patients with mCRPC (J Nucl Med, 2016), the first demonstration that a PSMA-targeted alpha emitter could produce deep responses where beta therapy and other options had failed.","refs":["clemens-kratochwil","ac225-psma"],"status":"historic"},{"era":"2020-2022","title":"PSMA PET and Pluvicto reach approval","description":"The FDA approves 68Ga-PSMA-11 on 1 December 2020 (UCSF and UCLA applications), the first PSMA PET agent approved in the US; Pylarify (piflufolastat F 18, Lantheus) follows on 26 May 2021 as the first commercially distributed PSMA PET agent. Pluvicto (177Lu-PSMA-617, Novartis) is approved 23 March 2022 for PSMA-positive mCRPC after androgen receptor pathway inhibition and taxane chemotherapy, based on VISION (38% reduction in risk of death), the first FDA-approved targeted radioligand therapy for prostate cancer.","refs":["ga68-psma-11","pylarify","pluvicto","vision","paper-vision-nejm-2021"],"status":"historic"},{"era":"2025","title":"Pluvicto moves to an earlier line","description":"The FDA expands the Pluvicto label on 28 March 2025, based on the PSMAfore trial, to adults with PSMA-positive mCRPC who have progressed on at least one androgen receptor pathway inhibitor and are considered appropriate to delay taxane chemotherapy, removing the prior-taxane requirement and roughly tripling the eligible US patient population.","refs":["psmafore","pluvicto"],"status":"current"},{"era":"2024-2028","title":"Alpha-emitting PSMA ligands after 177Lu-PSMA","description":"Two alpha-emitting PSMA ligands are in phase 2/3 development for patients progressing after 177Lu-PSMA therapy: FPI-2265 (225Ac-PSMA-I&T, Fusion Pharmaceuticals/AstraZeneca) in AlphaBreak, and AAA817 (225Ac-PSMA-617, Novartis) in a phase 3 programme including PSMAcTION (NCT06780670) and a combination trial with an androgen receptor pathway inhibitor (NCT06855277).","refs":["alphabreak","ac225-psma"],"status":"emerging"},{"era":"2028+","title":"Speculative: PSMA-directed therapy at diagnosis","description":"Ideas under discussion include PSMA-PET-guided metastasis-directed therapy as a curative strategy in oligorecurrent disease, alpha-emitting PSMA therapy at first metastatic diagnosis rather than after multiple prior lines, and using PSMA PET tumour volume as a formally qualified imaging biomarker for trials.","refs":["idea-psma-pet-guided-mdt","idea-alpha-first-mhspc","idea-tr2-psma-volume-qualification"],"status":"speculative"}],"watch":[{"item":"AAA817 + ARPI vs standard of care in PSMA-positive mCRPC, phase 3 primary completion","expected":"Primary Completion (Estimated): 2028-09-29","source":"https://clinicaltrials.gov/study/NCT06855277","refs":["novartis"]},{"item":"AAA817 vs standard of care after 177Lu-PSMA progression (PSMAcTION), primary completion","expected":"Primary completion date: Jun 27, 2028 (Anticipated)","source":"https://www.allclinicaltrials.com/study/NCT06780670","refs":["novartis"]},{"item":"AlphaBreak (FPI-2265) phase 2 primary completion","expected":"Estimated Completion: July 23, 2026","source":"https://www.ancora.ai/en/detailsradiopharm/NCT06402331","refs":["alphabreak","fusion-pharma"]}]},{"id":"radiopharma-roadmap","kind":"roadmap","name":"Radiopharmaceutical roadmap: iodine → lutetium → actinium","aka":[],"tldr":"The radiopharmaceutical roadmap runs eighty years from radioactive iodine for thyroid cancer to alpha-emitting drugs for prostate and neuroendocrine cancers, with isotope supply as the limiting factor.","summary":"The radiopharmaceutical roadmap runs from radioiodine curing differentiated thyroid cancer, the first theranostic, through radium-223 and Lutathera with its matched 68Ga-DOTATATE PET, to PSMA PET and Pluvicto building the first radioligand franchise. The current steps move Pluvicto and Lutathera into earlier lines amid an M&A wave, while the emerging step brings 225Ac and 212Pb alpha emitters and new targets such as FAP, GRPR, CAIX and B7-H3 into trials, with isotope supply as the limiting factor. The speculative end imagines radioligands as a standard modality with pan-cancer FAP theranostics and personalised dosimetry. The route links radioligand therapy, targeted alpha therapy, PSMA PET and FAPI PET, prostate, thyroid and neuroendocrine cancers, and the manufacturing bottleneck.","asOf":"2026-09-04","links":[{"label":"VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2107322"}],"tags":[],"related":["ga-68","ac-225","ra-223","pb-212"],"indications":[],"sections":[],"technologies":["radioligand-therapy","targeted-alpha-therapy","psma-pet","fapi-pet","radioimmunotherapy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1946-2000","title":"Radioiodine and early radioimmunotherapy","description":"131I cures differentiated thyroid cancer, the first theranostic. Strontium-89 and samarium-153 palliate bone pain. 90Y-ibritumomab and 131I-tositumomab (2002-03) work in lymphoma but fail commercially.","refs":["thyroid"],"status":"historic"},{"era":"2013-2018","title":"Radium-223 and Lutathera","description":"Radium-223 (ALSYMPCA, 2013) is the first alpha emitter approved, for bone metastases. 177Lu-DOTATATE (NETTER-1, 2018) establishes the modern peptide receptor radionuclide therapy paradigm with a matched 68Ga-DOTATATE PET.","refs":["lutathera","sstr2"],"status":"historic"},{"era":"2020-2022","title":"PSMA theranostics","description":"PSMA PET approved (68Ga-PSMA-11 2020, Pylarify 2021); Pluvicto approved (VISION, 2022). Novartis builds the first radioligand commercial franchise; supply and site-capacity constraints appear.","refs":["psma-pet","pluvicto","vision","pylarify"],"status":"current"},{"era":"2023-2026","title":"Earlier lines, consolidation, and an M&A wave","description":"PSMAfore moves Pluvicto pre-chemotherapy (2025), NETTER-2 moves Lutathera to first line (2024); 2026 label expansions. BMS buys RayzeBio ($4.1B), AstraZeneca buys Fusion ($2.4B), Lilly buys Point; Bayer, Sanofi, Novartis expand. Pylarify TruVu approved March 2026. ITM-11 reads out a positive phase 3.","refs":["psmafore","ryz101","fusion-pharma","rayzebio","itm"],"status":"current"},{"era":"2026-2029","title":"Alpha emitters and new targets","description":"225Ac-PSMA (Novartis, Bayer Trillium, Fusion FPI-2265), 225Ac-DOTATATE (RYZ101) and 212Pb-DOTAMTATE are in phase 3; FAP radioligands (FAP-2286) are in phase 2; GRPR, CAIX, B7-H3, DLL3 radioconjugates are in early trials. TerraPower's Philadelphia Ac-225 plant aims for a 20-fold supply increase. Dosimetry-guided dosing enters trials.","refs":["ac225-psma","ryz101","fap-2286","terrapower-isotopes","orano-med","dosimetry"],"status":"emerging"},{"era":"2029+","title":"Speculative: radioligands as a standard modality","description":"Alpha therapy in hormone-sensitive prostate cancer and after ADC failure; pan-cancer FAP theranostics; radio-ADCs and pretargeting; combination with PARP inhibitors, IO, and ADCs; automated decentralised radiopharmacies; total-body PET for ultra-low-dose dosimetry.","refs":["radioimmunotherapy","beta-then-alpha","pet-ct"],"status":"speculative"}],"watch":[]},{"id":"sstr-theranostics-roadmap","kind":"roadmap","name":"SSTR theranostics roadmap: octreotide scintigraphy → 68Ga-DOTATATE → 177Lu-DOTATATE → alpha","aka":[],"tldr":"Neuroendocrine tumours were the proving ground for the whole idea of theranostics: find a receptor on the tumour, image it with a low-dose radioactive scan, then treat with a matched higher-dose version of the same molecule. That sequence took thirty years to build and is now being extended with more powerful alpha-particle versions.","summary":"The somatostatin-receptor pathway is where theranostics as a field began. Indium-111 pentetreotide (OctreoScan), approved by the FDA on 2 June 1994, was the first peptide-based radiopharmaceutical approved for any indication, imaging somatostatin receptor 2 (SSTR2) on neuroendocrine tumours by gamma-camera scintigraphy. Gallium-68 dotatate (Netspot), approved 1 June 2016, replaced planar scintigraphy with quantitative PET, giving markedly better sensitivity for localising these often small, slow-growing tumours.\n\nThe therapeutic half of the pair, lutetium-177 dotatate (Lutathera), was approved by the FDA on 26 January 2018 on the strength of the NETTER-1 trial, becoming the first FDA-approved peptide receptor radionuclide therapy (PRRT) and confirming that the diagnostic-therapeutic pairing translates into a survival and progression-free-survival benefit, not just better pictures. The label was extended to first-line use in higher-grade (grade 2/3) tumours in 2024 on the strength of the NETTER-2 trial (72% reduction in risk of progression or death versus high-dose octreotide), and to adolescent patients (12 years and older) in April 2024, the first FDA-approved radiopharmaceutical for that age group.\n\nThe current frontier is alpha-emitting versions of the same pharmacophore for patients whose disease progresses after beta-emitting PRRT: 225Ac-DOTATATE (RYZ101) is in the phase 3 ACTION-1 trial, and 212Pb-DOTAMTATE (AlphaMedix) reported in October 2025 that its phase 2 ALPHAMEDIX-02 trial met all primary efficacy endpoints in both PRRT-naive and PRRT-exposed patients. A further extension under investigation is SSTR2-expressing meningioma, a non-oncological-in-the-classical-sense but SSTR2-driven tumour, where 68Ga-DOTATATE PET has been used since 2015 to delineate disease and 225Ac-DOTATATE (RYZ101) is now in an early-phase trial for progressive or recurrent intracranial meningioma.","asOf":"2026-09-22","links":[{"label":"FDA: Netspot (gallium Ga 68 dotatate) approval, June 2016","url":"https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208547Orig1s000Approv.pdf"},{"label":"FDA: Lutathera (lutetium Lu 177 dotatate) approval for GEP-NETs, January 2018","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lutetium-lu-177-dotatate-treatment-gep-nets"},{"label":"Novartis: NETTER-2 phase 3 results, first-line PRRT, January 2024","url":"https://www.novartis.com/us-en/news/media-releases/novartis-lutathera-significantly-reduced-risk-disease-progression-or-death-72-first-line-treatment-patients-advanced-gastroenteropancreatic-neuroendocrine-tumors"},{"label":"Sanofi: AlphaMedix (212Pb-DOTAMTATE) ALPHAMEDIX-02 phase 2 results, October 2025","url":"https://www.sanofi.com/en/media-room/press-releases/2025/2025-10-08-05-00-00-3163053"}],"tags":[],"related":["ga-68","in-111","lu-177","ac-225","pb-212"],"indications":["neuroendocrine","pancreatic-net","small-intestinal-net","meningioma"],"sections":[],"technologies":["sstr-pet","prrt","targeted-alpha-therapy"],"targets":["sstr2"],"drugs":["lutathera","ga68-dotatate","ryz101","alphamedix","itm-11"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["netter-1","action-1","alphamedix-02"],"people":[],"bottlenecks":[],"keyPapers":["paper-netter-1-nejm-2017","paper-netter-2-lancet-2024"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1994","title":"OctreoScan: the first peptide radiopharmaceutical","description":"The FDA approves indium-111 pentetreotide (OctreoScan, Mallinckrodt/Curium) on 2 June 1994 for scintigraphic localisation of neuroendocrine tumours bearing somatostatin receptors, the first radiolabelled peptide ever approved and the foundation of the theranostic principle in nuclear medicine.","refs":["neuroendocrine"],"status":"historic"},{"era":"2016","title":"68Ga-DOTATATE: PET replaces scintigraphy","description":"The FDA approves Netspot (a kit for gallium-68 dotatate injection, Advanced Accelerator Applications) on 1 June 2016 as the first gallium-68 PET agent, giving markedly better sensitivity than OctreoScan for localising somatostatin-receptor-positive neuroendocrine tumours.","refs":["ga68-dotatate","sstr-pet"],"status":"historic"},{"era":"2018","title":"Lutathera: the first approved PRRT","description":"The FDA approves lutetium Lu 177 dotatate (Lutathera) on 26 January 2018 for somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours, based on the NETTER-1 trial (79% reduction in risk of progression or death versus high-dose octreotide LAR), the first FDA-approved peptide receptor radionuclide therapy.","refs":["lutathera","netter-1","paper-netter-1-nejm-2017"],"status":"historic"},{"era":"2024","title":"NETTER-2 moves PRRT to first line","description":"The FDA expands the Lutathera label in 2024 to first-line use in newly diagnosed grade 2/3 advanced GEP-NETs, based on the NETTER-2 trial (72% reduction in risk of progression or death versus high-dose octreotide LAR alone), and separately approves Lutathera for pediatric patients 12 years and older in April 2024, the first FDA-approved radiopharmaceutical for that age group.","refs":["paper-netter-2-lancet-2024","lutathera"],"status":"historic"},{"era":"2022-2026","title":"Alpha-emitting SSTR radioligands after beta PRRT","description":"225Ac-DOTATATE (RYZ101) enters the phase 3 ACTION-1 trial for GEP-NETs progressing after 177Lu-DOTATATE/TOC. 212Pb-DOTAMTATE (AlphaMedix) receives FDA Breakthrough Therapy designation in 2024 and reports in October 2025 that its phase 2 ALPHAMEDIX-02 trial met all primary efficacy endpoints, with a 60% objective response rate in PRRT-naive patients.","refs":["action-1","alphamedix-02","ryz101","alphamedix"],"status":"current"},{"era":"2025-2028","title":"Emerging: SSTR2 theranostics in meningioma","description":"68Ga-DOTATATE PET, used since 2015 to delineate SSTR2-positive meningioma tissue from tumour-free tissue, is now the imaging companion for a therapeutic extension: 225Ac-DOTATATE (RYZ101) enters a trial for progressive or recurrent intracranial meningioma (grades 1-3) at Ohio State, testing whether the SSTR theranostic pairing extends beyond classic neuroendocrine tumours.","refs":["meningioma","sstr2"],"status":"emerging"},{"era":"2028+","title":"Speculative: antagonist ligands and earlier lines","description":"SSTR antagonist radioligands, which bind more receptor sites than the agonists (octreotide, DOTATATE) used to date, are proposed to increase tumour dose further. If alpha-emitting SSTR therapies read out positively, the sequence could extend to first-line use ahead of somatostatin analogues, and to indications such as SSTR-expressing breast cancer now in early trials.","refs":["idea-net-antagonist-ligands"],"status":"speculative"}],"watch":[{"item":"ACTION-1 (RYZ101) phase 3 primary completion","expected":"Primary Completion (Estimated): 2026-12","source":"https://clinicaltrials.gov/study/NCT05477576","refs":["action-1"]},{"item":"RYZ101 for progressive/recurrent intracranial meningioma, Ohio State trial","source":"https://clinicaltrials.gov/study/NCT07150806","refs":["meningioma"]}]}]