[{"id":"f-bone-targeted","kind":"section","name":"Bone-targeted radiopharmaceuticals","aka":[],"tldr":"Some radioactive drugs are built to home in on damaged bone rather than the tumour itself, easing bone pain from cancer that has spread to the skeleton and, in one case, helping patients live longer.","summary":"Bone-targeted radiopharmaceuticals exploit the fact that metastatic bone lesions have abnormally high bone turnover. Radium-223 dichloride behaves as a calcium mimetic, concentrating in newly formed bone matrix next to osteoblastic metastases, where its alpha-particle emissions cause localised DNA damage. It is the only bone-targeted radiopharmaceutical shown to extend overall survival: the phase 3 ALSYMPCA trial (921 patients with symptomatic, bone-predominant, castration-resistant prostate cancer without known visceral metastases) showed improved overall survival and delayed skeletal-related events against placebo plus best supportive care. Older agents — samarium-153 lexidronam and phosphorus-32 — and strontium-89 (not in wide current use) give palliative pain relief from bone metastases but have not shown a survival benefit.\n\nRadium-223's use has narrowed rather than widened since approval. The ERA-223 trial found that combining it with abiraterone and prednisone/prednisolone raised fracture incidence sharply (28.6% vs 11.4%) with no offsetting clinical benefit, so that combination is now contraindicated, and current guidance restricts radium-223 to bone-predominant mCRPC without visceral metastases, typically after at least two prior systemic therapies or in patients unfit for them. A phase 2 trial reported in 2026 (RADICAL, Alliance A031801, JCO) tested adding radium-223 to cabozantinib in bone-metastatic renal cell carcinoma and found no improvement in symptomatic skeletal event-free survival, progression-free survival or overall survival, and closed early for futility — a reminder that radium-223's prostate-cancer benefit does not automatically generalise to other bone-metastatic cancers.\n\nWhat remains unsolved: assessing whether radium-223 is actually working is harder than for most cancer drugs, because it does not shrink lesions in the way conventional RECIST-based imaging expects and its target is bone remodelling rather than the tumour directly; a 2026 review in Seminars in Nuclear Medicine surveys the resulting patchwork of serum biomarkers, liquid biopsy markers and imaging approaches (18F-fluoride PET/CT, whole-body diffusion MRI, PSMA PET/CT) used to judge response, without a single validated standard emerging.","asOf":"2026-09-22","links":[{"label":"ALSYMPCA trial (Parker et al., NEJM 2013)","url":"https://www.nejm.org/doi/10.1056/NEJMoa1213755"},{"label":"RADICAL trial (Alliance A031801): radium-223 + cabozantinib in mRCC (JCO, 27 Jul 2026)","url":"https://oncodaily.com/genitourinary-oncology/radical-2"},{"label":"Assessing therapeutic response to radium-223 (Semin Nucl Med, 2026)","url":"https://pubmed.ncbi.nlm.nih.gov/41412927/"},{"label":"Bone-targeting radionuclides in mCRPC: review of radium-223 combinations (Diagnostics, 2024)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11544963/"}],"tags":[],"related":["f-alpha-therapy","f-radioligand-therapy","f-18","ra-223","sm-153","sr-89","p-32"],"indications":["prostate-mcrpc","rcc","bone-metastases"],"sections":[],"technologies":["spect"],"targets":[],"drugs":["radium-223","samarium-153-lexidronam","phosphorus-32"],"companies":["bayer"],"institutions":[],"pathways":[],"terms":["bone-metastases"],"trials":["alsympca"],"people":[],"bottlenecks":[],"keyPapers":["paper-alsympca-radium-223-nejm-2013"],"journals":[],"dependsOn":[],"notes":["Radium-223 plus abiraterone/prednisone is contraindicated after ERA-223 found a sharply higher fracture rate (28.6% vs 11.4%) with no clinical benefit.","The 2026 RADICAL trial found no benefit from adding radium-223 to cabozantinib in bone-metastatic renal cell carcinoma, closing early for futility — radium-223's prostate-cancer survival benefit has not generalised to other tumour types tested so far.","There is no single validated method for assessing radium-223 response; conventional RECIST imaging is a poor fit because the drug targets bone remodelling rather than shrinking the tumour directly."],"order":10},{"id":"f-cardiac-imaging","kind":"section","name":"Cardiac imaging","aka":[],"tldr":"A radioactive tracer injected into the bloodstream lights up on a scanner wherever the heart muscle is getting enough blood flow, so doctors can see blocked arteries without surgery.","summary":"Nuclear cardiology's long-standing tools are SPECT myocardial perfusion imaging with technetium-99m agents, and PET perfusion imaging with 82Rb, 13N-ammonia or 15O-water, the last two requiring an on-site cyclotron or generator that limits which centres can offer PET perfusion at all. The field's biggest recent development is the FDA approval, on 27 September 2024, of flurpiridaz F-18 (Flyrcado, GE HealthCare/Lantheus) for PET myocardial perfusion imaging under rest or stress (pharmacologic or exercise) in adults with known or suspected coronary artery disease — the first new perfusion radiopharmaceutical approved by the FDA in nearly 30 years, based on the phase 3 AURORA trial and prior studies.\n\nFlurpiridaz's practical advantage is that, unlike 82Rb or 13N-ammonia, its 110-minute fluorine-18 half-life allows it to be manufactured centrally at a regional cyclotron and shipped as a unit dose to hospitals that have no cyclotron or generator of their own, which nuclear cardiology commentary expects to expand access to PET perfusion imaging considerably. It also allows quantification of absolute myocardial blood flow and myocardial flow reserve, similar to 13N-ammonia and 82Rb.\n\nWhat is still unresolved: the FDA approval of flurpiridaz explicitly does not change existing PET myocardial perfusion imaging appropriate-use criteria, so its clinical positioning relative to SPECT and to the older PET perfusion tracers is still being worked out in practice, and real-world access will depend on how widely regional cyclotron-supplied unit doses actually reach community hospitals rather than only academic centres with existing PET infrastructure.","asOf":"2026-09-22","links":[{"label":"FDA: approval of Flyrcado (flurpiridaz F 18) for myocardial ischemia/infarction evaluation, 27 Sep 2024","url":"https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-imaging-drug-evaluation-myocardial-ischemia-and-infarction"},{"label":"FLYRCADO prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=3bb6caf8-ac98-46c7-a9f0-961e66032705&type=display"},{"label":"FDA approval of 18F-flurpiridaz for PET: stepping into a new era of MPI (J Nucl Med, 2025)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12175995/"},{"label":"ASNC: F-18 flurpiridaz FDA approval announcement","url":"https://www.asnc.org/news/f18-flurpiridaz-fda-approval-nuclear-cardiologys-new-radiotracer-for-cardiac-pet-imaging/"}],"tags":[],"related":["f-molecular-imaging","f-18","tc-99m","n-13","o-15","rb-82"],"indications":[],"sections":[],"technologies":["pet","pet-ct","spect","spect-ct"],"targets":[],"drugs":[],"companies":["ge-healthcare","lantheus"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["FDA approval of flurpiridaz F-18 (Flyrcado, 27 September 2024) explicitly does not change existing PET myocardial perfusion appropriate-use criteria; its place in the diagnostic pathway relative to SPECT and older PET tracers is still being worked out.","Flurpiridaz's 110-minute half-life allows central cyclotron manufacture and unit-dose shipping, unlike 82Rb (generator-based) or 13N-ammonia (needs an on-site cyclotron); whether this actually expands access to community hospitals in practice is not yet demonstrated at scale."],"order":8},{"id":"f-dosimetry","kind":"section","name":"Dosimetry","aka":[],"tldr":"Dosimetry works out exactly how much radiation dose a patient's tumour and healthy organs actually receive, so treatment can in principle be tailored to the person rather than given as one fixed dose to everyone.","summary":"Most approved radioligand therapy today is given as a fixed activity on a fixed schedule — 7.4 GBq of 177Lu-PSMA-617 every six weeks for up to six cycles, or 7.4 GBq of 177Lu-DOTATATE every eight weeks for four cycles — regardless of how much radiation dose that delivers to an individual patient's tumour, kidneys or bone marrow. Reported organ doses vary widely between patients: EANM dosimetry committee data for 90Y-DOTATOC give roughly 1.7-2.8 Gy/GBq to the kidneys, compared with about 0.6-0.9 Gy/GBq for 177Lu-DOTATATE, and comparable heterogeneity is reported for PSMA ligands.\n\nPersonalised, dosimetry-guided dosing has clear proof of principle outside radioligand therapy: in the DOSISPHERE-01 trial of yttrium-90 radioembolisation for hepatocellular carcinoma, a personalised multi-compartment dosimetry approach (target ≥205 Gy to the tumour) produced a median overall survival of 26.6 months versus 10.7 months with standard single-compartment dosing (HR 0.42, Garin et al., Lancet Gastroenterol Hepatol 2021). Bringing that logic to radioligand therapy is technically harder because it needs serial SPECT/CT or blood sampling after each cycle, and pure beta-emitters like 90Y have no gamma emission for direct imaging.\n\nThe field has not reached consensus on whether this is worth mandating. EANM's 2025 response to the EMA's concept paper on clinical evaluation of therapeutic radiopharmaceuticals states plainly that \"given the current lack of conclusive clinical evidence,\" it does not hold a definitive position on recommending extensive individual dosimetry, simplified approaches, or fixed-activity posology, and asks regulators not to mandate dose-planned prescribing until the evidence and harmonised methods exist. This is the single biggest open methodological question in the field: whether individualised dosimetry meaningfully improves outcomes enough to justify its cost and complexity in routine practice, versus in trials only.","asOf":"2026-09-22","links":[{"label":"EANM reply to EMA concept paper on clinical evaluation of therapeutic radiopharmaceuticals (Jan 2025)","url":"https://eanm.org/wp-content/uploads/2025/02/EANM-Reply-to-the-public-consultation-on-the-European-Medicines-Agency-Concept-paper-on-clinical-evaluation-of-therapeutic-radiopharmaceuticals-in-oncology.pdf"},{"label":"DOSISPHERE-01 trial (Garin et al., Lancet Gastroenterol Hepatol 2021)","url":"https://www.onclive.com/view/personalized-radioembolization-improves-os-vs-standard-dosing-in-advanced-hcc"},{"label":"EANM dosimetry committee recommendations for 177Lu-labelled SSTR- and PSMA-targeting ligands","url":"https://eanm.org/publications/guidelines/overview/dosimetry/"}],"tags":[],"related":["f-radioligand-therapy","f-radioembolisation","f-regulation-reimbursement","lu-177","y-90"],"indications":["neuroendocrine","hcc","prostate-mcrpc"],"sections":[],"technologies":["radioligand-dosimetry","in-vivo-dosimetry","quantitative-imaging-biomarkers"],"targets":[],"drugs":[],"companies":[],"institutions":["eanm","snmmi"],"pathways":[],"terms":["dosimetry","gray-unit"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["EANM's own 2025 position is that it does not have enough conclusive clinical evidence to recommend mandatory individual dosimetry over fixed-activity dosing for radioligand therapy.","DOSISPHERE-01 is the clearest randomised proof that personalised dosimetry changes outcomes, but it is a radioembolisation trial, not a radioligand-therapy trial; the same case has not yet been made with equivalent rigour for 177Lu-PSMA or 177Lu-DOTATATE.","Pure beta-emitters without a useful gamma line (e.g. 90Y) cannot be imaged directly for dosimetry, which is a physical, not just logistical, constraint on personalising some regimens."],"order":6},{"id":"f-infection-imaging","kind":"section","name":"Infection & inflammation imaging","aka":[],"tldr":"The same FDG tracer used to find cancer also lights up sites of infection and inflammation, which helps doctors find hidden abscesses, infected joint replacements or heart-valve infections that scans and blood tests alone can miss.","summary":"FDG PET/CT is now the best-evidenged nuclear medicine tool for infection and inflammation outside oncology, formalised in the EANM/SNMMI guideline/procedure standard for [18F]FDG hybrid PET use in infection and inflammation in adults, version 2.0 (Abikhzer et al., Eur J Nucl Med Mol Imaging 2025), which defines protocols and interpretation criteria across 19 indications, from bacteraemia and suspected spondylodiscitis to endocarditis, vascular graft infection and periprosthetic joint infection. For periprosthetic joint infection specifically, a pooled analysis cited in the guideline reports FDG PET sensitivity of about 85% and specificity of about 86% across 23 studies (1,437 patients), and the guideline states that the absence of periprosthetic uptake reliably excludes infection in both hip and knee prostheses, while a positive scan needs careful interpretation because aseptic loosening, recent surgery and metal-related artefact can all cause false-positive uptake.\n\nWhite blood cell scintigraphy remains the preferred confirmatory test when FDG PET/CT is inconclusive, particularly for prosthetic joint and vascular graft infection, because it retains higher specificity than FDG in that specific setting even though FDG PET/CT is now the first-line hybrid imaging test for most of the 19 defined indications. A separate EANM/EBJIS/ESR consensus document (with ESCMID endorsement) sets out the broader multimodality diagnostic pathway for prosthetic joint infection, in which nuclear imaging is one component alongside clinical, microbiological and structural imaging criteria.\n\nWhat the 2025 guideline explicitly flags as unresolved: it found insufficient evidence to support FDG PET/CT as a standard indication for COVID-19 (including long COVID), interstitial lung disease, or inflammatory arthropathies and myopathies, while noting evidence may emerge in future. SUV and target-to-background ratios, validated as semi-quantitative measures in oncology, have not been generally validated for distinguishing infection from sterile inflammation or malignancy and the guideline says they should be used with caution.","asOf":"2026-09-22","links":[{"label":"EANM/SNMMI guideline/procedure standard for FDG hybrid PET in infection and inflammation v2.0 (Eur J Nucl Med Mol Imaging, 2025)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11732780/"},{"label":"JNM summary: EANM/SNMMI FDG hybrid PET infection/inflammation guideline v2.0","url":"https://jnm.snmjournals.org/content/early/2025/02/06/jnumed.125.269538"},{"label":"EANM: Inflammation/Infection guideline overview page","url":"https://eanm.org/publications/guidelines/overview/inflammation-infection/"}],"tags":[],"related":["f-molecular-imaging","f-18"],"indications":[],"sections":[],"technologies":["fdg-pet","spect","gamma-probes-dose-calibrators"],"targets":[],"drugs":["fludeoxyglucose-f18","technetium-sulfur-colloid","tilmanocept-tc99m"],"companies":[],"institutions":["eanm","snmmi"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["The 2025 EANM/SNMMI guideline found insufficient evidence to add COVID-19 (including long COVID), interstitial lung disease, or inflammatory arthropathies/myopathies as supported indications, though it leaves the door open as evidence accumulates.","SUV and target-to-background ratios are not generally validated for distinguishing infection from sterile inflammation or malignancy, unlike their established role in oncology; the guideline recommends caution.","White blood cell scintigraphy keeps a role as the confirmatory test when FDG PET/CT is inconclusive, especially around prosthetic joints, because false-positive FDG uptake from aseptic loosening or recent surgery is a recognised limitation."],"order":9},{"id":"f-isotope-supply","kind":"section","name":"Isotope supply","aka":[],"tldr":"The radioactive ingredients in these medicines are made in a small number of ageing reactors and accelerators worldwide, and demand is now growing faster than that supply.","summary":"Every radiopharmaceutical begins as an isotope made in a reactor or accelerator, and the whole field sits on a genuinely fragile production base. Roughly 95% of the world's molybdenum-99 (the parent of technetium-99m, used in about 30 million SPECT scans a year, 80% of all nuclear medicine imaging) comes from a handful of research reactors in South Africa, the Netherlands, Belgium and Australia; because Mo-99's half-life is 66 hours it cannot be stockpiled, so a reactor outage cancels scans within days (OECD-NEA, 2025 review of medical radioisotope supply).\n\nLutetium-177 demand rose sharply after Pluvicto's approval, and the OECD-NEA and IAEA both project that non-carrier-added Lu-177 production capacity will not keep pace with clinical demand; a key bottleneck is enriched ytterbium-176 target material, historically sourced mainly from Russia. New capacity is being built to close the gap: Canada's Darlington reactor began isotope production runs (Mo-99, Lu-177, Y-90) from 2025; India's Dhruva reactor supplies domestic Lu-177 and imports the shortfall from Russia; SHINE Technologies (Chrysalis facility, Wisconsin) is targeting over 75% of US Mo-99 demand with a $263 million DOE conditional loan commitment, and is already producing Lu-177; and Eden Radioisotopes has filed a US NRC construction permit for a new Mo-99/Lu-177 facility aiming to supply up to 50% of global Mo-99 demand.\n\nActinium-225 has its own, much tighter, constraint (see the alpha-therapy front): global supply of roughly 63 GBq/year against rising clinical trial demand. Ideas circulating to fix the underlying fragility include a coordinated international reserve and shared production schedule across the world's medical isotope reactors, Western enrichment capacity for ytterbium-176 so Lu-177 has more than one supplier, and a global isotope supply observatory that forecasts shortages before they hit clinics.","asOf":"2026-09-22","links":[{"label":"OECD-NEA: Current trends in the supply and utilisation of medical radioisotopes (2025)","url":"https://www.oecd-nea.org/upload/docs/application/pdf/2025-10/7743_medical_radioisotopes_supply_rev.pdf"},{"label":"Eden Radioisotopes files NRC construction permit for Mo-99/Lu-177 facility (ANS, May 2026)","url":"https://www.ans.org/news/2026-05-08/article-8016/eden-targets-domestic-medical-radioisotope-production/"},{"label":"IAEA/OECD-NEA: Towards a robust supply chain for medical radioisotopes","url":"https://inis.iaea.org/records/06vmc-y0w54"}],"tags":[],"related":["f-alpha-therapy","f-radiochemistry","f-radioligand-therapy","tc-99m","mo-99","lu-177","ac-225","y-90"],"indications":[],"sections":[],"technologies":["therapy-isotope-supply-chain","research-reactor-isotope-production","cyclotron-isotope-production","actinium-225-supply","radiopharmacy-network"],"targets":[],"drugs":[],"companies":["ansto","ire","nordion","northstar-medical-radioisotopes","shine-technologies","terrapower-isotopes","isotopia","curium"],"institutions":["iaea"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Mo-99's 66-hour half-life means it cannot be stockpiled; the physics of decay, not inventory management, sets the logistics of the whole Tc-99m supply chain.","Enriched ytterbium-176, the target material for non-carrier-added Lu-177, has historically depended heavily on Russian supply; Western enrichment capacity is only now being built out.","PALLAS/OECD-NEA modelling projects Lu-177 demand outpacing available capacity from around 2025 onward without new reactor investment."],"order":4},{"id":"f-molecular-imaging","kind":"section","name":"Molecular imaging","aka":[],"tldr":"Molecular imaging uses a small radioactive tracer injected into the body and a PET or SPECT camera to show where a specific protein sits on a tumour, so doctors can pick the right treatment and check it is working.","summary":"Molecular imaging is the diagnostic half of theranostics: a radiolabelled ligand binds a target expressed on tumour cells (PSMA, SSTR2, FAP, HER2, CAIX, TROP2 and others) and a PET/CT or PET/MRI camera maps its distribution across the whole body. The field's biggest single deployment is PSMA PET in prostate cancer: the joint EANM/SNMMI PSMA PET/CT procedure guideline 2.0 (Fendler et al., Eur J Nucl Med Mol Imaging 2023) and the 2026 NCCN guidelines now recommend PSMA PET ahead of conventional imaging for unfavourable intermediate- and high-risk staging and for biochemical recurrence, and require it to select patients for PSMA-targeted radioligand therapy. The 2020 proPSMA trial (Hofman et al., Lancet) established the head-to-head case against CT and bone scan.\n\nSomatostatin receptor (SSTR) PET with 68Ga-DOTATATE or DOTATOC plays the equivalent gatekeeping role for peptide receptor radionuclide therapy in neuroendocrine tumours, and FAPI PET is being explored as a pan-cancer stromal imaging agent, though it does not yet have the guideline weight of PSMA or SSTR PET. FDG PET remains the workhorse general-oncology tracer and the comparator against which every newer agent is judged.\n\nWhat is unsolved in 2026: PSMA expression is heterogeneous and a meaningful fraction of mCRPC patients are PSMA-negative or discordant on biopsy, so imaging-based patient selection is an imperfect proxy for radioligand therapy response; quantitative reporting (SUV, PROMISE/miTNM, E-PSMA) is still not uniformly applied across sites; and reimbursement for newer PET tracers lags their guideline recommendation in several health systems. Total-body PET and AI-assisted reading are being investigated to cut dose and scan time but are not yet standard of care.","asOf":"2026-09-22","links":[{"label":"EANM/SNMMI: PSMA PET/CT procedure guideline 2.0 (Eur J Nucl Med Mol Imaging, 2023)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10027805/"},{"label":"proPSMA trial (Hofman et al., Lancet 2020)","url":"https://pmc.ncbi.nlm.nih.gov/articles/"},{"label":"PMC: Future opportunities and nuances with PSMA PET (2026 review, incl. 2026 NCCN guidance)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13141699/"}],"tags":[],"related":["f-radioligand-therapy","f-dosimetry","ga-68"],"indications":["prostate","prostate-bcr","prostate-high-risk","neuroendocrine","rcc"],"sections":[],"technologies":["psma-pet","sstr-pet","fdg-pet","fapi-pet","pet-ct","pet-mri","immuno-pet","caix-pet","her2-pet","trop2-pet","quantitative-imaging-biomarkers","total-body-pet-screening"],"targets":[],"drugs":["ga68-psma-11","pylarify","flotufolastat","psma-1007-f18","ga68-dotatate","fludeoxyglucose-f18","girentuximab-zr89","fluoroestradiol-f18","illuccix","locametz"],"companies":["telix","lantheus","curium","blue-earth-diagnostics","novartis","ge-healthcare","siemens-healthineers","united-imaging","isotopia","sofie-biosciences"],"institutions":[],"pathways":[],"terms":["suv","theranostics"],"trials":["propsma"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["PSMA-negative or discordant disease on biopsy is not resolved by better tracers alone; it is a biology problem, not a chemistry one.","Quantitative reporting frameworks (PROMISE/miTNM, E-PSMA) exist but adoption across sites is uneven, which limits cross-trial comparability.","Reimbursement for newer PET agents (e.g. flotufolastat, PSMA-1007) trails clinical guideline endorsement in several countries."],"order":1},{"id":"f-neuro-imaging","kind":"section","name":"Neuro-imaging","aka":[],"tldr":"Brain PET scans can now show the sticky protein clumps of Alzheimer's disease directly, and are also used to see how far a brain tumour has spread and whether radiotherapy scarring looks like tumour regrowth.","summary":"Amyloid and tau PET are the most consequential recent additions to neuro-imaging: the 2025 Appropriate Use Criteria from the Alzheimer's Association and SNMMI (updated from 2013, published simultaneously in Alzheimer's & Dementia and the Journal of Nuclear Medicine) rated 7 of 17 clinical scenarios as appropriate for amyloid PET and 5 of 17 for tau PET, chiefly assessment and prognosis of mild cognitive impairment, working up dementia of unclear cause, and determining eligibility for and monitoring response to anti-amyloid immunotherapies. Under the 2024 Alzheimer's Association diagnostic criteria, amyloid PET is a \"Core 1\" biomarker sufficient to establish the diagnosis, while tau PET is a \"Core 2\" biomarker used to stage disease once diagnosis is established.\n\nFDG PET keeps a distinct, complementary role in distinguishing Alzheimer's disease from other dementia subtypes by its regional pattern of hypometabolism, and is also used in neuro-oncology to help separate tumour recurrence from radiation necrosis after treatment for glioma or meningioma, a distinction that is often difficult on structural MRI alone. Somatostatin receptor PET (68Ga-DOTATATE) has become the imaging standard for meningioma, matching the joint EANM/EANO/RANO/SNMMI theranostics practice guideline that also covers SSTR-ligand radionuclide therapy for meningioma.\n\nWhat remains unsolved: expanded reimbursement for amyloid and tau PET has improved access in the US, but availability and payer coverage still vary widely internationally, and the AUC explicitly discourage use of these scans outside a proper dementia-specialist workup (for example, they are rated rarely appropriate for asymptomatic people who simply carry the APOE4 risk gene). Radiation necrosis after stereotactic radiotherapy remains genuinely difficult to distinguish from recurrent tumour even with modern PET tracers in a meaningful minority of cases.","asOf":"2026-09-22","links":[{"label":"Updated Appropriate Use Criteria for Amyloid and Tau PET (J Nucl Med / Alzheimer's & Dementia, 2025)","url":"https://jnm.snmjournals.org/content/early/2025/01/07/jnumed.124.268756"},{"label":"SNMMI news release: updated AUC for amyloid and tau PET (Jan 2025)","url":"https://snmmi.org/Web/Web/News/Articles/SNMMI-and-the-Alzheimer-s-Association-Release-Updated-Appropriate-Use-Criteria-for-Amyloid-and-Tau-P.Mobile.aspx"},{"label":"PET imaging in Alzheimer disease in the era of antiamyloid therapy (J Nucl Med Technol, 2026)","url":"https://pubmed.ncbi.nlm.nih.gov/41667280/"}],"tags":[],"related":["f-molecular-imaging","f-dosimetry","ga-68"],"indications":["glioblastoma","meningioma"],"sections":[],"technologies":["pet","pet-ct","pet-mri","sstr-pet","fdg-pet"],"targets":[],"drugs":[],"companies":["ge-healthcare","siemens-healthineers","canon-medical"],"institutions":["snmmi"],"pathways":[],"terms":["radiation-necrosis"],"trials":[],"people":["peter-bartenstein"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["The 2025 SNMMI/Alzheimer's Association AUC explicitly discourage amyloid or tau PET in people with no cognitive impairment, even if they carry the APOE4 risk allele, and in place of genetic testing for suspected causal mutations.","Distinguishing radiation necrosis from tumour recurrence on PET after brain radiotherapy remains genuinely difficult in a meaningful minority of cases; no single tracer resolves it definitively.","Coverage and access for amyloid/tau PET have expanded in the US but remain uneven internationally."],"order":7},{"id":"f-radiochemistry","kind":"section","name":"Radiochemistry & manufacturing","aka":[],"tldr":"Making one of these medicines means attaching a radioactive atom to a targeting molecule and getting it sterile and out the door within hours, before it decays away — a manufacturing problem unlike almost any other medicine.","summary":"Radiopharmaceutical chemistry starts by conjugating a chelator (most commonly DOTA or DOTAGA for metal radionuclides) onto a targeting ligand — a peptide, small molecule or antibody — via amine, thiol or click chemistry, then radiolabelling it with the chosen isotope, purifying it and formulating a sterile, injectable dose, all under current Good Manufacturing Practice. Antibody-based agents (e.g. 89Zr- or 177Lu-labelled antibodies) traditionally use random lysine conjugation, which gives a heterogeneous chelator-to-antibody ratio; site-specific conjugation methods are increasingly used to improve consistency and preserve binding affinity, though the benefit has to be demonstrated for each individual product (EJNMMI Radiopharm Chem, 2024).\n\nRegulatorily, radiopharmaceuticals are treated as their own category: the EMA's draft revised guideline on the quality of radiopharmaceuticals (consultation closed 30 April 2026) sets out that manufacturing dossiers must describe the process from the nuclear transformation step onward, and that radionuclidic and radiochemical impurities need their own control strategy distinct from ordinary small-molecule drug substances. In the UK, amended Clinical Trials Regulations (in force 28 April 2026) set out which manufacturing and QP-certification steps for radiopharmaceutical investigational medicinal products can be split between an MIA(IMP) licence holder and an MS-licensed radiolabelling site.\n\nThe unresolved manufacturing problem is scale-up: batch sizes are defined by total radioactivity rather than mass, decay clocks run throughout production and shipping, and sterility testing often cannot be completed before a short-lived product must be released and administered, which is why radiopharmaceutical GMP release strategies (parametric release, real-time release testing) are an active area rather than a solved one.","asOf":"2026-09-22","links":[{"label":"EMA draft guideline on the quality of radiopharmaceuticals, revision 2 (consultation closed 30 April 2026)","url":"https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-radiopharmaceuticals-revision-2_en.pdf"},{"label":"Good practices for 89Zr radiopharmaceutical production and conjugation (EJNMMI Radiopharm Chem, 2024)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11088613/"},{"label":"MHRA: GMP and radiopharmaceutical investigational medicinal products guidance (updated 28 April 2026)","url":"https://www.gov.uk/guidance/clinical-trials-for-medicines-good-manufacturing-practice-and-radiopharmaceutical-investigational-medicinal-products"}],"tags":[],"related":["f-isotope-supply","f-regulation-reimbursement","zr-89","lu-177"],"indications":[],"sections":[],"technologies":["medical-cyclotrons-synthesis-modules","radiopharmaceutical-gmp-release","site-specific-conjugation","sterile-fill-finish","radionuclide-generators-kits","pet-tracer-manufacturing"],"targets":[],"drugs":[],"companies":["trasis","comecer","eckert-ziegler","iba","jubilant-radiopharma","curium","nucleus-radiopharma","evergreen-theragnostics"],"institutions":["ema","mhra"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Sterility testing of short-lived radiopharmaceuticals often cannot be completed before the product must be released and injected, because the isotope decays before the assay returns — this is a structural, not a compliance, problem.","Site-specific conjugation improves consistency over random lysine labelling for antibody-based agents, but the clinical benefit has to be shown for each product individually; it is not yet a universal standard.","The EMA's revised radiopharmaceutical quality guideline (public consultation closed April 2026) has not yet been finalised as of this record's date."],"order":5},{"id":"f-radioembolisation","kind":"section","name":"Radioembolisation","aka":[],"tldr":"Radioembolisation delivers tiny radioactive beads directly into the blood vessels feeding a liver tumour through a catheter, so the radiation stays concentrated in the liver instead of spreading through the whole body.","summary":"Transarterial radioembolisation (TARE), also called selective internal radiation therapy (SIRT), delivers yttrium-90-loaded microspheres (glass, e.g. TheraSphere, or resin, e.g. SIR-Spheres) through a hepatic artery catheter to treat unresectable hepatocellular carcinoma, and is also used for liver-dominant metastases from colorectal cancer and neuroendocrine tumours. The pivotal SARAH and SIRveNIB trials tested Y-90 TARE against sorafenib in advanced HCC and found radioembolisation was not superior to systemic therapy on survival, which tempered early enthusiasm for TARE as a stand-alone replacement for systemic treatment in advanced disease.\n\nThe practice-changing development since has been personalised dosimetry. The randomised phase 2 DOSISPHERE-01 trial compared a standard single-compartment dosing approach (target 120±20 Gy to the perfused liver lobe) against a personalised multi-compartment approach targeting at least 205 Gy to the tumour in locally advanced HCC, and found median overall survival of 26.6 months with personalised dosing versus 10.7 months with standard dosing (HR 0.42, 95% CI 0.22-0.83, p=0.0096), with objective response 71.4% versus 35.7% and 36% of personalised-arm patients downstaged to surgery versus 4% in the standard arm (Garin et al., Lancet Gastroenterol Hepatol 2021). This has shifted practice guidance toward partition-model dosimetry using pre-treatment MAA SPECT rather than fixed body-surface-area dosing.\n\nWhat is still unsettled: TARE's role relative to newer systemic options (immunotherapy combinations, TACE) in intermediate-stage disease is being re-tested in ongoing trials combining radioembolisation with checkpoint inhibitors (e.g. durvalumab and bevacizumab), and while personalised dosimetry clearly improves outcomes in the DOSISPHERE-01 population, routine adoption of partition-model dosimetry across centres worldwide is uneven, similar to the dosimetry debate in radioligand therapy.","asOf":"2026-09-22","links":[{"label":"DOSISPHERE-01 trial (Garin et al., Lancet Gastroenterol Hepatol 2021)","url":"https://www.onclive.com/view/personalized-radioembolization-improves-os-vs-standard-dosing-in-advanced-hcc"},{"label":"DOSISPHERE-01 data sheet (Boston Scientific)","url":"https://www.bostonscientific.com/content/dam/bostonscientific/pi/portfolio-group/cancer-therapies/therasphere/resource-center/clinical-data/DOSISPHERE-01_Data_Sheet.pdf"},{"label":"Advances and emerging techniques in Y-90 radioembolisation for HCC (Cancers, 2025)","url":"https://www.mdpi.com/2072-6694/17/9/1494"}],"tags":[],"related":["f-dosimetry","f-bone-targeted","y-90"],"indications":["hcc","hcc-intermediate"],"sections":[],"technologies":["radioembolisation-tare"],"targets":[],"drugs":[],"companies":["sirtex","boston-scientific"],"institutions":[],"pathways":[],"terms":["tare"],"trials":["sarah-sirvenib","nct06040099"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["SARAH and SIRveNIB both found Y-90 TARE was not superior to sorafenib on survival in advanced HCC, so TARE has not replaced systemic therapy in that setting.","DOSISPHERE-01 is the clearest randomised evidence that personalised, partition-model dosimetry meaningfully changes outcomes in radioembolisation (median OS 26.6 vs 10.7 months), but routine uptake of this dosimetry approach still varies by centre.","Trials combining TARE with checkpoint inhibitors and anti-angiogenics (e.g. durvalumab/bevacizumab, NCT06040099) are testing whether locoregional and systemic immunotherapy combine safely and effectively; results are pending."],"order":11},{"id":"f-radioligand-therapy","kind":"section","name":"Radioligand therapy","aka":[],"tldr":"Radioligand therapy attaches a radioactive particle to a molecule that homes in on a tumour, so the radiation is delivered from the inside of the cancer rather than from an external beam.","summary":"Radioligand therapy (RLT) with beta-emitters is the most clinically mature branch of theranostics. Lutetium-177 vipivotide tetraxetan (Pluvicto, 177Lu-PSMA-617) is approved by the FDA and EMA for PSMA-positive metastatic castration-resistant prostate cancer, on the strength of the VISION trial (median overall survival 15.3 vs 11.3 months, HR 0.62; radiographic progression-free survival 8.7 vs 3.4 months, HR 0.40; Sartor et al., NEJM 2021) and the earlier-line PSMAfore trial (rPFS 9.3 vs 5.6 months, HR 0.41), which supported the FDA's March 2025 label expansion into taxane-naive mCRPC. Lutetium-177 dotatate (Lutathera) is approved for gastroenteropancreatic neuroendocrine tumours on the basis of NETTER-1 (Strosberg et al., NEJM 2017) and has since been extended to a first-line setting by NETTER-2 (Lancet 2024).\n\nA competitive multi-agent PSMA-RLT field is emerging behind Pluvicto: 177Lu-PSMA-I&T (PNT2002, Lantheus/POINT Biopharma) reported the SPLASH trial, and Telix's antibody-based rosopatamab tetraxetan (TLX591-Tx) is in the ProstACT Global phase 3 programme. On the neuroendocrine side, 177Lu-edotreotide (ITM-11) and FAP-targeted 177Lu-FAP-2286 are in later-phase development.\n\nWhat remains unsolved: a 2026 GRADE-assessed meta-analysis of six randomised trials (Mubarika et al., Int Urol Nephrol 2026) found the primary intention-to-treat overall-survival benefit of 177Lu-PSMA over standard of care was not statistically significant (HR 0.81, 95% CI 0.62-1.06), with a benefit only apparent after adjusting for control-arm crossover (HR 0.76, 95% CI 0.59-0.96) — a reminder that trial-design choices, not just the isotope, drive the reported benefit. Optimal sequencing against androgen-receptor pathway inhibitors, taxanes and alpha emitters is still being worked out in trials such as PSMAddition and ENZA-p, and lutetium-177's roughly 0.5-2 mm beta path length is thought to undertreat isolated tumour cells and micrometastases, motivating the move to alpha emitters.","asOf":"2026-09-22","links":[{"label":"FDA label: Pluvicto (accessdata.fda.gov)","url":"https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215833s000lbl.pdf"},{"label":"VISION trial (Sartor et al., NEJM 2021)","url":"https://www.nejm.org/doi/10.1056/NEJMoa2107322"},{"label":"GRADE-assessed meta-analysis of 177Lu-PSMA RCTs (Int Urol Nephrol, 2026)","url":"https://pubmed.ncbi.nlm.nih.gov/42570199/"},{"label":"Guideline of guidelines: 177Lu-PSMA RLT (BJU Int, 2026)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13458634/"}],"tags":[],"related":["f-molecular-imaging","f-alpha-therapy","f-dosimetry","lu-177"],"indications":["prostate-mcrpc","prostate-mhspc","neuroendocrine","small-intestinal-net","pancreatic-net","lung-net"],"sections":[],"technologies":["radioligand-therapy","lu177-radioligand-therapy","prrt","peptide-drug-conjugate","psma-pet","sstr-pet"],"targets":[],"drugs":["pluvicto","lutathera","lu177-psma-it","itm-11","fap-2286"],"companies":["novartis","advanced-accelerator-applications","point-biopharma","lantheus","itm","telix"],"institutions":[],"pathways":[],"terms":["prrt-term","psa50","mcrpc-mhspc"],"trials":["vision","psmafore","netter-1","splash","psmaddition"],"people":[],"bottlenecks":[],"keyPapers":["paper-vision-nejm-2021","paper-netter-1-nejm-2017","paper-netter-2-lancet-2024"],"journals":[],"dependsOn":[],"notes":["A 2026 GRADE meta-analysis found the ITT overall-survival benefit of 177Lu-PSMA vs standard of care was not significant (HR 0.81, 95% CI 0.62-1.06) until adjusted for crossover (HR 0.76, 95% CI 0.59-0.96); trial design materially changes the reported effect size.","Optimal sequencing of RLT against ARPIs, taxanes and alpha emitters is unresolved; PSMAddition and ENZA-p are testing earlier and combined use.","177Lu's beta path length (roughly 0.5-2 mm) is thought to leave isolated tumour cells and micrometastases undertreated, which is the main argument for moving to alpha emitters."],"order":2},{"id":"f-regulation-reimbursement","kind":"section","name":"Regulation & reimbursement","aka":[],"tldr":"Getting one of these radioactive medicines approved and then actually paid for is its own specialised process, separate from ordinary drugs, and the rules for who pays what changed again for 2026 in the US.","summary":"Radiopharmaceuticals are regulated as a distinct drug category. In the US, the FDA reviews and approves them under the same statutory framework as other drugs but with radiopharmaceutical-specific guidance on chemistry, manufacturing and controls; in the EU the EMA's guideline on the quality of radiopharmaceuticals is being revised (draft revision 2, public consultation closed 30 April 2026) to update how manufacturing dossiers describe the process from radionuclide production onward and how radionuclidic/radiochemical impurities are controlled. The UK's MHRA updated its clinical-trials GMP guidance for radiopharmaceutical investigational medicinal products, effective 28 April 2026, clarifying which manufacturing and QP-certification steps can be split between licensed facilities.\n\nPayment is a separate and increasingly consequential fight, especially in the US Medicare system. Under the CY2026 Hospital Outpatient Prospective Payment System final rule, CMS raised the per-day cost threshold above which diagnostic radiopharmaceuticals are paid separately (using hospital-claims-derived mean unit cost) from $630 to $655, continuing a policy that packages lower-cost diagnostic tracers into the payment for the imaging procedure itself rather than paying for them separately — a policy nuclear medicine societies have long argued undervalues newer, higher-cost diagnostic agents. CMS also created a new $10-per-dose add-on payment, effective 1 January 2026, for technetium-99m doses derived from domestically produced molybdenum-99 (HCPCS code C9176, requiring at least 50% of the Mo-99 to have been both irradiated and processed in the US), replacing an earlier add-on that had rewarded non-highly-enriched-uranium production regardless of country of origin. Separately payable therapeutic radiopharmaceuticals without pass-through status continue to be paid at ASP+6%, falling back to WAC+3% or 95% of AWP when ASP or WAC data are unavailable.\n\nWhat remains unresolved: ASP (average sales price) reporting for diagnostic radiopharmaceuticals is still voluntary under CMS rules for 2026, which limits how accurately the mean-unit-cost proxy reflects true market prices, and CMS says it \"intends to explore\" updated ASP-reporting guidance without having committed to a firm change. Medicare's coverage-with-evidence-development pathway continues to gate access to some newer radiopharmaceuticals pending real-world outcomes data, and reimbursement policy differs enough between the US, the EU (EMA/national payers) and other regulators (Japan's PMDA, the UK's MHRA) that global access to a newly approved agent can lag its first approval by years.","asOf":"2026-09-22","links":[{"label":"CMS: Hospital Outpatient Prospective Payment System, January 2026 update (MM14361)","url":"https://www.cms.gov/files/document/mm14361-hospital-outpatient-prospective-payment-system-january-2026-update.pdf"},{"label":"Sidley: Medicare payment policy final rule for outpatient setting addresses radiopharmaceuticals (Dec 2025)","url":"https://www.sidley.com/en/insights/newsupdates/2025/12/medicare-payment-policy-final-rule-for-outpatient-setting-addresses-radiopharmaceuticals"},{"label":"EMA: draft guideline on the quality of radiopharmaceuticals, revision 2","url":"https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-radiopharmaceuticals-revision-2_en.pdf"},{"label":"MHRA: clinical trials GMP and radiopharmaceutical IMPs guidance (updated 28 April 2026)","url":"https://www.gov.uk/guidance/clinical-trials-for-medicines-good-manufacturing-practice-and-radiopharmaceutical-investigational-medicinal-products"}],"tags":[],"related":["f-radiochemistry","f-dosimetry","f-isotope-supply","tc-99m","mo-99"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":["ema","mhra","pmda","snmmi","eanm"],"pathways":[],"terms":["medicare-ced"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["ASP reporting for diagnostic radiopharmaceuticals remains voluntary under the CY2026 OPPS rule; CMS says it intends to explore updated guidance but has not mandated reporting.","The $10 domestic-Mo-99 add-on payment (HCPCS C9176, effective 1 Jan 2026) replaced an earlier add-on tied to non-HEU production rather than country of origin — a policy shift toward reshoring rather than just proliferation-resistant production methods.","Regulatory and reimbursement timelines are not synchronised across the US, EU, UK and Japan, so global patient access to a newly approved radiopharmaceutical can lag its first approval by a substantial margin."],"order":12},{"id":"f-alpha-therapy","kind":"section","name":"Targeted alpha therapy","aka":[],"tldr":"Alpha therapy uses a heavier type of radioactive particle that travels only a few cell widths but hits much harder, aimed at cancer cells that have stopped responding to the gentler beta-particle treatments.","summary":"Targeted alpha therapy (TAT) conjugates an alpha-emitting radionuclide, most often actinium-225, to the same PSMA or somatostatin-receptor ligands used in beta radioligand therapy. Alpha particles have a short tissue range (tens of micrometres, a few cell diameters) but a much higher linear energy transfer than beta particles, so they cause dense, largely non-repairable double-strand DNA breaks. Radium-223 (Alpharadin), an alpha-emitting bone-seeking agent, was the first alpha emitter approved in oncology, on the basis of the ALSYMPCA trial (improved overall survival and delayed skeletal-related events in bone-predominant mCRPC).\n\nFor tumour-targeted alpha therapy, 225Ac-PSMA agents (including Fusion Pharmaceuticals' FPI-2265 in the AlphaBreak programme, and RayzeBio/BMS's RYZ101, 225Ac-DOTATATE, for neuroendocrine tumours) are in phase 1/2 development, largely in patients who progressed on or are refractory to lutetium-177 therapy. A 2026 systematic review and meta-analysis (Belabaci et al., Eur J Nucl Med Mol Imaging 2026) assessed combined 225Ac/177Lu-PSMA therapy but the field still lacks randomised phase 3 evidence for any alpha-PSMA agent.\n\nThe defining unsolved problem is supply, not biology: global 225Ac production is estimated at roughly 63 GBq (1.7 Ci) per year, sufficient for only about 100-200 patients annually, against an estimated clinical and trial demand of around 185 GBq/year and rising (Alpha Atlas / IAEA TECDOC-2057, 2024). Production depends on a handful of 229Th generators (Oak Ridge National Laboratory, the EU Joint Research Centre in Karlsruhe, and Russia's IPPE) or on cyclotron irradiation of 226Ra, and the IAEA's Global Radium-226 Management Initiative is recovering legacy radium sources from around 80 countries as an alternative feedstock. Xerostomia (salivary gland uptake) and dosimetric uncertainty are the main clinical limitations reported so far.","asOf":"2026-09-22","links":[{"label":"IAEA TECDOC-2057: Production and quality control of actinium-225 radiopharmaceuticals (2024)","url":"https://www-pub.iaea.org/MTCD/publications/PDF/TE-2057web.pdf"},{"label":"ALSYMPCA trial (Parker et al., NEJM 2013)","url":"https://www.nejm.org/doi/10.1056/NEJMoa1213755"},{"label":"IAEA: Global Radium-226 Management Initiative update (ANS, Jan 2026)","url":"https://www.ans.org/news/2026-01-14/article-7675/iaeas-global-radium226-management-initiative-continues-to-progress/"},{"label":"Actinium-225/Bismuth-213 supply and application barriers (Cancers, 2025)","url":"https://www.mdpi.com/2072-6694/17/18/3055"}],"tags":[],"related":["f-radioligand-therapy","f-isotope-supply","f-bone-targeted","lu-177","ac-225","ra-223"],"indications":["prostate-mcrpc","neuroendocrine","metastatic-ppgl"],"sections":[],"technologies":["targeted-alpha-therapy","actinium-225-supply","astatine-211-alpha-therapy","alpha-nanogenerators"],"targets":[],"drugs":["ac225-psma","fpi-2265","ryz101","alphamedix","radium-223"],"companies":["fusion-pharma","rayzebio","perspective-therapeutics","orano-med","actinium-pharmaceuticals","artbio","convergent-therapeutics"],"institutions":[],"pathways":[],"terms":["alpha-vs-beta"],"trials":["alsympca","alphabreak","nct05219500"],"people":[],"bottlenecks":[],"keyPapers":["paper-alsympca-radium-223-nejm-2013"],"journals":[],"dependsOn":[],"notes":["Global 225Ac supply (~63 GBq/year) covers only about 100-200 patient treatments a year against an estimated demand of ~185 GBq/year and rising (IAEA TECDOC-2057, 2024).","No alpha-PSMA agent has randomised phase 3 evidence yet; current clinical use is investigational or salvage after lutetium-177.","The IAEA's Global Radium-226 Management Initiative is recovering legacy radium sources from roughly 80 countries as feedstock for 225Ac, a genuinely new supply route rather than incremental reactor capacity."],"order":3}]