The state of the art and future perspectives of new radionuclides in Nuclear Medicine continue to evolve, driven by the development of isotopes with innovative applications in theragnostics. In this second part of the continuing education series, the clinical and therapeutic applications of terbium, actinium, and bismuth are analyzed in depth. The use of the four terbium isotopes (terbium-149, terbium-152, terbium-155, and terbium-161) is described, offering a versatile system for both diagnosis and treatment due to their chemical similarity to lutetium-177, along with the challenges related to their production and availability. Additionally, actinium-225, a powerful alpha-emitting radionuclide, is reviewed for its growing role in Targeted Alpha Therapy (TAT), particularly in prostate cancer and neuroendocrine tumors. Finally, bismuth-213, derived from actinium-225, is analyzed for its short half-life, making it a viable option for localized and selective therapies. Despite technical and production challenges, these radionuclides are driving the evolution of precision medicine, expanding therapeutic and diagnostic possibilities in Nuclear Medicine.

The therapeutic landscape for neuroendocrine tumors (NETs) has rapidly evolved over the last three decades with the influx of a myriad of treatment options, such as somatostatin analogs (SSAs), targeted therapies, alkylating chemotherapies, and radioligand therapy (RLT). While the advent and regulatory approval of beta emitting RLT such as 177Lu-DOTATATE has offered a valuable therapeutic option for patients with NETs, there is still very significant room to tap the maximal therapeutic potential of RLT. Alpha RLT agents such as RYZ101 (225Ac-DOTATATE) offer a potential advantage over beta RLT due to more complex double-stranded DNA breaks and targeted cytotoxicity, as well as potential for minimizing off-target side-effects. Existing pre-clinical and clinical data suggest promising safety and efficacy of RYZ101 among patients with NETs. The ongoing phase 1b/3 trial ACTION-1 is poised to compare the safety and efficacy of RYZ101 against standard care therapies in advanced gastroenteropancreatic NETs (Ki67 ≤ 20%), after disease progression of prior 177Lu-SSA therapy. Yet, other alpha RLT agents are currently being investigated in both RLT-naïve as well-pre-treated patient populations. While long-term safety and efficacy data are awaited, alpha RLT agents such as RYZ101 offer a unique opportunity to enhance the therapeutic promise of RLT in NETs.

Targeted charged alpha- and beta-particle therapies are currently being used in clinical radiation treatments as newly developed methods for either killing or controlling tumor cell growth. The alpha particles can be generated either through a nuclear decay reaction or in situ by a nuclear fission reaction such as the boron neutron capture reaction. Different strategies have been employed to improve the selectivity and delivery of radiation dose to tumor cells based on the source of the clinically used alpha particles. As a result, the side effects of the treatment can be minimized. The increasing attention and research efforts on targeted alpha-particle therapy have been fueled by exciting results of both academic research and clinical trials. It is highly anticipated that alpha-particle therapy will improve the efficacy of treating malignant tumors. In this overview, we compare radionuclide drug conjugates (RDC) with boron neutron capture therapy (BNCT) to present recent developments in targeted alpha-particle therapy.

Effective therapeutic strategies for advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) remain challenging, including a lack of response to therapy and post-treatment relapse. The rapid development of targeted radionuclide therapy (TRT) offers promising data for patients with somatostatin receptor (SSTR)-expressing tumors. This approach exhibits more advantages than somatostatin analog (SSA) therapy, which is primarily effective for well-differentiated and slow-growing GEP-NENs. Fortunately, some clinical studies on peptide receptor radionuclide therapy (PRRT) labeled with α-emitting radionuclides for GEP-NENs patients showed effective results for those with more advanced GEP-NENs, or those with malignant metastasis. For the improvement of clinical efficacy and the decline in the incidence of treatment-related relapse, recent progress in developing novel techniques and effective disease management strategies for optimal targeting has led to the emergence of targeted alpha therapy (TAT) in GEP-NENs patients. For instance, labeled technology and combination therapy could contribute to significantly improved long-term outcomes. However, the exact dosimetry for precision oncology, the shortage of radionuclides, and the stability of disease control are still under careful consideration. More high-quality, large-scale prospective studies are essential for obtaining valuable evidence on challenging problems and for further exploration.

Recent years have seen a swift rise in the use of α-emitting radionuclides such as 225Ac and 223Ra as various radiopharmaceuticals to treat (micro)metastasized tumors. They have shown remarkable effectiveness in clinical practice owing to the highly cytotoxic α-particles that are emitted, which have a very short range in tissue, causing mainly double-stranded DNA breaks. However, it is essential that both chelation and targeting strategies are optimized for their successful translation to clinical application, as α-emitting radionuclides have distinctly different features compared to β--emitters, including their much larger atomic radius. Furthermore, upon α-decay, any daughter nuclide irrevocably breaks free from the targeting molecule, known as the recoil effect, dictating the need for faster targeting to prevent healthy tissue toxicity. In this review we provide a brief overview of the current status of targeted α-therapy and highlight innovations in α-emitter-based chelator design, focusing on the role of click chemistry to allow for fast complexation to biomolecules at mild labeling conditions. Finally, an outlook is provided on different targeting strategies and the role that pre-targeting can play in targeted alpha therapy.

Terbium-149 is a short-lived α-particle emitter, potentially useful for tumor-targeted therapy. The aim of this study was to investigate terbium-149 in combination with the somatostatin receptor (SSTR) agonist DOTATATE and the SSTR antagonist DOTA-LM3. The radiopeptides were evaluated to compare their therapeutic efficacy in vitro and in vivo.

Terbium-149 was produced at ISOLDE/CERN and chemically purified at the Paul Scherrer Institute. Radiolabeling of somatostatin analogues with [149Tb]TbCl3 was performed under standard labeling conditions at pH 4.5. Cell viability (MTT) and survival assays (colony forming) assays were performed after 16-18 h exposure of SSTR-positive AR42J rat pancreatic tumor cells to various activity concentrations of [149Tb]Tb-DOTATATE and [149Tb]Tb-DOTA-LM3. DNA double-strand breaks were determined using immunofluorescence imaging of γ-H2A.X and 53BP1. Therapy studies were performed with AR42J tumor-bearing mice injected with 1 × 5 MBq or 2 × 5 MBq of the respective radiopeptide. The tolerability of up to 40 MBq [149Tb]Tb-DOTATATE or 40 MBq [149Tb]Tb-DOTA-LM3 was assessed with regard to undesired effects to the bone marrow and kidneys in immunocompetent mice without tumors.

The radiolabeling of peptides was achieved at molar activities of up to 20 MBq/nmol at ≥ 98% radiochemical purity. AR42J cell viability was reduced in an activity-dependent manner, with [149Tb]Tb-DOTA-LM3 being slightly more potent than [149Tb]Tb-DOTATATE (EC50: 0.5 vs. 1.2 kBq/mL). Both radiopeptides induced a similar number of γ-H2A.X and 53BP1 foci per nuclei, which indicated DNA damage in AR42J tumor cells. Injection of tumor-bearing mice with 1 × 5 MBq radiopeptide resulted in median survival times of 16.5 days and 19 days for [149Tb]Tb-DOTATATE and [149Tb]Tb-DOTA-LM3, respectively, as compared to only 8 days for untreated control mice. Application of 2 × 5 MBq of the radiopeptides further extended the median survival times to 30 days and 29 days, respectively. The blood cell counts and values for blood plasma biomarkers of treated mice without tumors were similar to those of untreated controls. Renal accumulation of [99mTc]Tc-DMSA was similar in all mice, indicating normal kidney function.

149Tb-based radiopeptides effectively reduced the viability of tumor cells in vitro as well as the tumor growth in mice without causing relevant adverse events, irrespective of whether the SSTR agonist or antagonist was employed. These data encourage further preclinical application of terbium-149 to evaluate its potential in combination with other tumor-targeting agents.

The incidence and prevalence of neuroendocrine tumours (NETs) are on the rise, but to date, only complete surgical resection is curative. Among the various therapeutic options for metastatic disease, peptide receptor radionuclide therapy (PRRT), linking a radioactive moiety to an octreotide derivative, has been shown to be highly efficacious and a well-tolerated therapy, improving progression-free survival and prolonging overall survival. Nevertheless, complete responses are rare, and the current β-particle emitters have non-optimal radiobiological properties. A new generation of α-particle-emitting radionuclides is being developed, with the advantages of very high energy and a short path length. We survey the most recent developments in this field, summarising the result of currently performed studies in this potentially ground-breaking novel form of therapy for NETs.

Neuroendocrine tumors encompass a wide range of tumors which originate from neural crest cells. These tumors were thought to be rare tumors, however, with the advent of advanced diagnostic techniques along with better understanding of the clinical presentation and histology of these tumors, the incidence of these tumors is exponentially rising. As the incidence and detection rate of NENs increased, the concept of 'heterogeneity' came into picture, which in turn led to dual-tracer imaging with addition of FDG PET/CT. Despite an imaging-based decision-making approach for NENs, there is still a significant subset of patients where the imaging-based biomarkers fall short in disease assessment, prognostication and improving outcomes. Alternate pathways as well as better peptide vectors for targeting the somatostatin receptor need to be studied. In this article, we address the existing as well as emerging trends in radiopharmaceuticals used for NENs, which are likely to impact not just the diagnostic algorithms in future, but also management strategies.

Prostate-specific membrane antigen (PSMA) radioligand therapy (PRLT) has become a promising option for treating metastatic castration-resistant prostate cancer (mCRPC). Radioligands labelled with the 68Ga/177Lu theranostic pair have been most widely used in the clinic for diagnosis and therapy, respectively. This study aims to develop a novel PSMA-targeted radioligand, LNC1011, radiolabeled with alpha-emitter 225Ac, to optimise pharmacokinetic properties and assess its potential for targeted alpha therapy (TAT) in prostate cancer treatment.

LNC1011 (Dan-PSMA) was synthesised based on a PSMA-binding ligand with the addition of a dansylated amino acid. Systematic radiochemical analyses were conducted to confirm the successful synthesis and radiolabelling of [225Ac]Ac-LNC1011. Cell uptake and competition binding assays were performed in PSMA-positive PC3-PIP tumour cells to evaluate the binding affinity and PSMA targeting specificity. The pharmacokinetics properties and tumour uptake were characterised by biodistribution studies using healthy mice and a PC3-PIP xenograft mouse model injected with [225Ac]Ac-LNC1011. Radioligand therapy studies and maximum tolerated dose (MTD) assays were conducted to systematically evaluate the therapeutic efficacy and the safety of [225Ac]Ac-LNC1011.

[225Ac]Ac-LNC1011 was successfully radiolabelled with high radiochemical purity (> 97%) and high stability within 96 h (radiochemical purity > 96%). The high binding affinity of LNC1011 (IC50 = 16.28 nM) to PSMA was comparable to that of PSMA-617 (IC50 = 27.93 nM). Biodistribution studies confirmed that [225Ac]Ac-LNC1011 had moderate blood elimination half-life (T1/2z = 13.4 ± 0.57 h), which was at an optimised level between [225Ac]Ac-PSMA-617 (T1/2z = 5.19 ± 0.12 h) and [225Ac]Ac-PSMA-EB-01 (T1/2z = 25.18 ± 2.78 h). In addition, high tumour uptake of [225Ac]Ac-LNC1011 was identified to be 38.28 ± 10.04%ID/g at 1 h post-injection. The specific uptake gradually increased and peaked at 24 h (80.57 ± 3.00%ID/g) and persisted at a high level up to 72 h post-injection (50.58 ± 5.37%ID/g). Targeted alpha therapy results showed the complete inhibition of PC3-PIP tumour growth after administration of a single dose of 1 µCi and 0.5 µCi of [225Ac]Ac-LNC1011 similar to 0.5 µCi [225Ac]Ac-PSMA-617. At the 0.1 µCi dose level, partial remission was observed for [225Ac]Ac-LNC1011, as recurrence was found 20 days after administration. In contrast, mice treated with 0.1 µCi [225Ac]Ac-PSMA-617 showed incomplete tumour inhibition under the same conditions.

[225Ac]Ac-LNC1011 was successfully radiolabelled with high radiochemical purity and stability. With significantly improved tumour uptake and retention over PSMA-617, [225Ac]Ac-LNC1011 showed significantly better therapeutic efficacy than [225Ac]Ac-PSMA-617 for targeted alpha therapy of prostate cancer.

Hepatic metastases are a major cause of morbidity and mortality for patients with cancer. Apart from curative resection, which offers patients the potential for long-term survival, an array of locoregional therapies, with limited evidence of improving survival, are used to treat them. The authors use examples from the realm of gastrointestinal cancer, largely focusing on the experience of patients with neuroendocrine cancer, hepatobiliary cancer, and colorectal cancer, to suggest that current systemic therapies offer, at minimum, similar survival outcomes for patients compared with these locoregional approaches.

Despite the effectiveness of 177 Lu-based peptide receptor radionuclide therapy in treating metastatic neuroendocrine tumors (NETs), disease progression posttreatment remains a significant challenge. Targeted alpha therapy (TAT) has emerged as a promising option for patients experiencing such progression. This study aims to assess the therapeutic efficiency and toxicity of TAT in patients with metastatic NET through a meta-analysis.

We conducted a comprehensive search of PubMed, Embase, Cochrane Library, and CINAHL using relevant keywords. The analysis focused on the pooled proportions of objective response rate (ORR) and disease control rate (DCR) to determine therapeutic efficiency. We also evaluated the incidence of serious hematologic and renal adverse events (grade 3 or 4) to assess toxicity. A subgroup analysis was performed to identify factors influencing therapeutic outcomes.

Our meta-analysis included 7 studies comprising 162 patients. The results showed that TAT achieved ORR of 49.5% (95% confidence interval [CI]: 41.7%-57.4%) and DCR of 87.0% (95% CI: 72.1%-96.8%). The incidences of hematologic and renal toxicities were low, at 2.1% (95% CI: 0.5%-5.5%) and 3.4% (95% CI: 1.2%-7.3%), respectively. Subgroup analysis indicated consistent therapeutic efficiency across different variables, including prior 177 Lu-based peptide receptor radionuclide therapy treatment, 225 Ac-based TAT, absence of radiosensitizer, and methods of response evaluation, with ORR ranging from 46.6% to 57.1% and DCR from 82.0% to 91.5%.

TAT is an effective treatment for metastatic NET, demonstrating substantial disease control and response rates with minimal toxicity. These findings suggest that TAT is a viable therapeutic alternative for patients with metastatic NET.

Although peptide radionuclide therapy (PRRT) using a somatostatin analog (SSA) radiolabeled with a beta- emitter: [177Lu]Lu-DOTATATE has shown a good clinical efficacy in neuroendocrine tumors (NETs), most of the patients only achieved tumoral stabilization and rare but severe long-term hematological toxicities have been reported. One of the promising options to improve PRRT is targeted alpha therapy. It is therefore essential to propose animal models that can mimic systemic spread disease, especially microscopic disease such as early stage of NET liver metastases to explore targeted alpha therapy. Herein, we report the evaluation of efficacy and toxicity of [225Ac]Ac-DOTATOC in an original preclinical murine model simulating the development of well-characterized liver metastases of pancreatic NETs with SSTR overexpression.

A mouse model of liver metastases of pancreatic NETs was developed by intraportal injection of AR42J cells and explored using [68 Ga]Ga-DOTATOC and [18F]F-FDG PET/MRI. Biodistribution study and radiation dosimetry of [225Ac]Ac-DOTATOC were determined in subcutaneous tumor-bearing NMRI-nude mice. Efficacy and toxicity were determined by intravenous injection of increasing activities of [225Ac]Ac-DOTATOC 10 days after intraportal graft.

Liver tumors showed a high uptake of [68 Ga]Ga-DOTATOC and no uptake of [18F]F-FDG confirming the well-differentiated phenotype. All groups treated with [225Ac]Ac-DOTATOC showed a significant increase in overall survival compared with DOTATOC-treated mice, especially those treated with the highest activities: 53 days with 240 kBq (p = 0.0001), and 58 days with 2 × 120 kBq (p < 0.0001) vs 28 days with non-radiolabeled DOTATOC. On blood tests, a transient and moderate decreased in white blood cells count after treatment and no severe hepatic or renal toxicity were observed after treatment which was consistent with pathological and radiation dosimetry findings.

[225Ac]Ac-DOTATOC exhibit a favorable efficacy and toxicity profile in a mouse model of liver micrometastatic pancreatic NET.

Background: Alpha radionuclide therapy has emerged as a promising novel strategy for cancer treatment; however, the therapeutic potential of 225Ac-labeled peptides in pancreatic cancer remains uninvestigated. Methods: In the cytotoxicity study, tumor cells were incubated with 225Ac-DOTA-RGD2. DNA damage responses (γH2AX and 53BP1) were detected using flowcytometry or immunohistochemistry analysis. Biodistribution and therapeutic studies were carried out in BxPC-3-bearing mice. Results: 225Ac-DOTA-RGD2 demonstrated potent cytotoxicity against cells expressing αvβ3 or αvβ6 integrins and induced G2/M arrest and γH2AX expression as a marker of double-stranded DNA breaks. 225Ac-DOTA-RGD2 (20, 40, 65, or 90 kBq) showed favorable pharmacokinetics and remarkable tumor growth inhibition without severe side effects in the BxPC-3 mouse model. In vitro studies revealed that 5 and 10 kBq/mL of 225Ac-DOTA-RGD2 swiftly induced G2/M arrest and elevated γH2AX expression. Furthermore, to clarify the mechanism of successful tumor growth inhibition for a long duration in vivo, we investigated whether short-term high radiation exposure enhances radiation sensitivity. Initially, a 4 h induction treatment with 5 and 10 kBq/mL of 225Ac-DOTA-RGD2 enhanced both cytotoxicity and γH2AX expression with 0.5 kBq/mL of 225Ac-DOTA-RGD2 compared to a treatment with only 0.5 kBq/mL of 225Ac-DOTA-RGD2. Meanwhile, the γH2AX expression induced by 5 or 10 kBq/mL of 225Ac-DOTA-RGD2 alone decreased over time. Conclusions: These findings highlight the potential of using 225Ac-DOTA-RGD2 in the treatment of intractable pancreatic cancers, as its ability to induce G2/M cell cycle arrest enhances radiosensitization, resulting in notable growth inhibition.

Radiopharmaceuticals are drugs used in treatment or diagnosis that contain a radioactive part, usually a pharmaceutical part in their structure. Adverse drug reactions are harmful and unexpected responses that occur when administered at normal doses. Although radiopharmaceuticals are regarded as safe medical products, adverse reactions should not be ignored. More serious adverse reactions such as myelosuppression, pleural effusion, and death may develop in therapeutic radiopharmaceuticals due to their use at higher doses than those used in diagnosis. Therefore, monitoring adverse reactions and reporting them to health authorities is important. This review aims to provide information about adverse reactions that may be related to radiopharmaceuticals used in treatment.

Nuclear medicine therapy offers a promising approach for tumor treatment, as the energy emitted during radionuclide decay causes irreparable damage to tumor cells. Notably, α-decay exhibits an even more significant destructive potential. By conjugating α-nuclides with antibodies or small-molecule inhibitors, targeted alpha therapy (TAT) can enhance tumor destruction while minimizing toxic side effects, making TAT an increasingly attractive antineoplastic strategy. Astatine-211 ( 211At) and actinium-225 ( 225Ac) have emerged as highly effective agents in TAT due to their exceptional physicochemical properties and biological effects. In this review, we highlight the applications of 211At-/ 225Ac-radiopharmaceuticals, particularly in specific tumor targets, such as prostate-specific membrane antigen (PSMA) in prostate cancers, cluster of differentiation (CD) in hematological malignancies, human epidermal growth factor receptor-2 (HER2) in ovarian cancers, and somatostatin receptor (SSTR) in neuroendocrine tumors. We synthesize the progress from preclinical and clinical trials to provide insights into the promising potential of 211At-/ 225Ac-radiopharmaceuticals for future treatments.

Targeted radionuclide therapy (TRT) for internal pathway-directed treatment is a game changer for precision medicine. TRT improves tumor control while minimizing damage to healthy tissue and extends the survival for patients with cancer. The application of theranostic-paired TRT along with cellular phenotype and genotype correlative analysis has the potential for malignant disease management. Chelation chemistry is essential for the development of theranostic-paired radiopharmaceuticals for TRT. Among image-guided TRT, 68Ga and 99mTc are the current standards for diagnostic radionuclides, while 177Lu and 225Ac have shown great promise for β- and α-TRT, respectively. Their long half-lives, potent radiobiology, favorable decay schemes, and ability to form stable chelation conjugates make them ideal for both manufacturing and clinical use. The current challenges include optimizing radionuclide production processes, coordinating chelation chemistry stability of theranostic-paired isotopes to reduce free daughters [this pertains to 225Ac daughters 221Fr and 213Bi]-induced tissue toxicity, and improving the modeling of micro dosimetry to refine dose-response evaluation. The empirical approach to TRT delivery is based on standard radionuclide administered activity levels, although clinical trials have revealed inconsistent outcomes and normal-tissue toxicities despite equivalent administered activities. This review presents the latest optimization methods for chelation-based theranostic radiopharmaceuticals, advancements in micro-dosimetry, and SPECT/CT technologies for quantifying whole-body uptake and monitoring therapeutic response as well as cytogenetic correlative analyses.

Targeted alpha therapy (TAT) of somatostatin receptor-2 (SSTR2) positive neuroendocrine tumors (NETs) involving Ac-225 ([225Ac]Ac-DOTA-TATE) has previously demonstrated improved therapeutic efficacy over conventional beta particle-emitting peptide receptor radionuclide therapy agents. DOTA-TATE requires harsh radiolabeling conditions for chelation of [225Ac]Ac3+, which can limit the achievable molar activities and thus therapeutic efficacy of such TAT treatments. Macropa-TATE was recently highlighted as a potential alternative to DOTA-TATE, owing to the mild radiolabeling conditions and high affinity toward [225Ac]Ac3+; however, elevated liver and kidney uptake were noted as a major limitation and a suitable imaging radionuclide is yet to be reported, which will be required for patient dosimetry studies and assessment of therapeutic benefit. Previously, [155Tb]Tb-crown-TATE has shown highly effective imaging of NETs in preclinical SPECT/CT studies, with high tumor uptake and low non-target accumulation; these favourable properties and the versatile coordination behavior of the crown chelator may therefore show promise for combination with Ac-225 for TAT.

Crown-TATE was labeled with Ac-225, and radiochemical yield was analyzed as the function of crown-TATE concentration. LogD7.4 was measured as the indication of hydrophilicity. Free [225Ac]Ac3+ release from [225Ac]Ac-crown-TATE in human serum was studied. Biodistribution studies of [225Ac]Ac-crown-TATE in mice bearing AR42J tumors was evaluated at 1, 4, 24, 48, and 120 h, and the absorbed dose to major organs calculated. Therapy-monitoring studies with AR42J tumor bearing mice were undertaken using 30 kBq and 55 kBq doses of [225Ac]Ac-crown-TATE and compared to controls treated with PBS or crown-TATE.

[225Ac]Ac-crown-TATE was successfully prepared with high molar activity (640 kBq/nmol), and characterized as a moderately hydrophilic radioligand (LogD7.4 = -1.355 ± 0.135). No release of bound Ac-225 was observed over 9 days in human serum. Biodistribution studies of [225Ac]Ac-crown-TATE showed good initial tumor uptake (11.1 ± 1.7% IA/g at 4 h) which was sustained up to 120 h p.i. (6.92 ± 2.03% IA/g). Dosimetry calculations showed the highest absorbed dose was delivered to the tumors. Therapy monitoring studies demonstrated significant (log-rank test, P < 0.005) improved survival in both treatment groups compared to controls.

This preclinical study demonstrated the therapeutic efficacy of [225Ac]Ac-crown-TATE for treatment of NETs, and highlights the potential of using crown chelator for stable chelation of Ac-225 under mild conditions.

Bifunctional chelators (BFCs) are vital in the design of effective radiopharmaceuticals, as they are able to bind to both a radiometal ion and a targeting vector. The 3p-C-NETA or 4-[2-(bis-carboxy-methylamino)-5-(4-nitrophenyl)-entyl])-7-carboxymethyl-[1,4,7]tri-azonan-1-yl acetic acid is a novel and promising BFC, developed for diagnostic and therapeutic purposes. The binding affinity between the BFC and radiometal ion significantly impacts their effectiveness. Predicting the equilibrium constants for the formation of 1:1 radiometals/chelator complexes (log K1 values) is crucial for designing BFCs with improved affinity and selectivity for radiometals. The purpose of this study is to evaluate the complexation of Ga3+, Tb3+, Bi3+, and Ac3+ radiometal ions with 3p-C-NETA using density functional theory (B3LYP and M06-HF functional) and 6-311G(d)/SDD basis sets, where the 1,4,7,10-tetrazacyclodecane-1,4,7,10-tetracetic acid (DOTA) was employed as a benchmark. Formation of the [Ac3+(3p-C-NETA)(H2O)]- complexes is predicted to be markedly less stable compared to the other complexes, exhibiting the lowest chemical hardness and the highest chemical softness. Additionally, the chelation stability of the complexes is mainly determined by ligand-ion and ion-water interactions, which depend on the atomic charge and atomic radius of the metal ion.

Objective.225Ac radiopharmaceuticals have tremendous potential for targeted alpha therapy, however,225Ac (t1/2= 9.9 d) lacks direct gamma emissions forin vivoimaging.226Ac (t1/2= 29.4 h) is a promising element-equivalent matched diagnostic radionuclide for preclinical evaluation of225Ac radiopharmaceuticals.226Ac has two gamma emissions (158 keV and 230 keV) suitable for SPECT imaging. This work is the first feasibility study forin vivoquantitative226Ac SPECT imaging and validation of activity estimation.Approach.226Ac was produced at TRIUMF (Vancouver, Canada) with its Isotope Separator and Accelerator (ISAC) facility. [226Ac]Ac3+was radiolabelled with the bioconjugate crown-TATE developed for therapeutic targeting of neuroendocrine tumours. Mice with AR42J tumour xenografts were injected with either 2 MBq of [226Ac]Ac-crown-TATE or 4 MBq of free [226Ac]Ac3+activity and were scanned at 1, 2.5, 5, and 24 h post injection in a preclinical microSPECT/CT. Quantitative SPECT images were reconstructed from the 158 keV and 230 keV photopeaks with attenuation, background, and scatter corrections. Image-based226Ac activity measurements were assessed from volumes of interest within tumours and organs of interest. Imaging data was compared withex vivobiodistribution measured via gamma counter.Main results. We present, to the best of our knowledge, the first everin vivoquantitative SPECT images of226Ac activity distributions. Time-activity curves derived from SPECT images quantify thein vivobiodistribution of [226Ac]Ac-crown-TATE and free [226Ac]Ac3+activity. Image-based activity measurements in the tumours and organs of interest corresponded well withex vivobiodistribution measurements.Significance. Here in, we established the feasibility ofin vivo226Ac quantitative SPECT imaging for accurate measurement of actinium biodistribution in a preclinical model. This imaging method could facilitate more efficient development of novel actinium labelled compounds by providing accurate quantitativein vivopharmacokinetic information essential for estimating toxicities, dosimetry, and therapeutic potency.

Neuroendocrine neoplasms (NENs) are a diverse group of tumors that express neuroendocrine markers and primarily affect the lungs and digestive system. The incidence of NENs has increased over time due to advancements in imaging and diagnostic techniques. Effective management of NENs requires a multidisciplinary approach, considering factors such as tumor location, grade, stage, symptoms, and imaging findings. Treatment strategies vary depending on the specific subtype of NEN. In this review, we will focus on treatment strategies and therapies including the information relevant to clinicians in order to undertake optimal management and treatment decisions, the implications of different therapies on imaging, and how to ascertain their possible complications and treatment effects.

Peptide receptor radionuclide therapy (PRRT) has become mainstream therapy of metastatic neuroendocrine tumors not controlled by somatostatin analog therapy. Currently, beta particle-emitting radiopharmaceuticals are the mainstay of PRRT. Alpha particle-emitting radiopharmaceuticals have a theoretic advantage over beta emitters in terms of improved therapeutic efficacy due to higher cancer cell death and lower nontarget tissue radiation-induced adverse events due to shorter path length of alpha particles. We discuss the available evidence for and the role of alpha particle PRRT.

Neuroendocrine neoplasms (NENs) are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are the most common subtype of NENs. Historically, GEP-NENs have been regarded as infrequent and slow-growing malignancies; however, recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades. In addition, an increasing number of studies have proven that GEP-NENs result in a limited life expectancy. These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed. Therefore, there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs. In this review, we have summarized the limitations and recent advancements in our comprehension of the epidemiology, clinical presentations, pathology, molecular biology, diagnosis, and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients.

We aimed to evaluate the efficacy and safety of 225 Ac-DOTATATE targeted α therapy (TAT) in various neuroendocrine neoplasms (NENs) with high somatostatin receptor (SSTR) expression.

This single-center prospective study included 10 patients with histologically diagnosed NENs that exhibited increased SSTR expression on 68 Ga-DOTATATE PET/CT imaging. All patients received 225 Ac-DOTATATE TAT. The primary end points were molecular imaging-based response and disease control rate (DCR), measured using the slightly modified Positron Emission Tomography Response Criteria in Solid Tumors 1.0. The secondary end points were adverse event profiles and clinical responses. The adverse event profile was determined according to the Common Terminology Criteria for Adverse Events version 5.0. Clinical response was assessed using the EORTC QLQ-C30 v3.0 (European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire version 3.0).

A molecular imaging-based partial response was observed in 40% of all patients, SD in 40%, PD in 20%, and DCR in 80%. The DCR was 83.3% (5/6) in patients who were previously treated with 177 Lu-DOTATATE. According to the EORTC QLQ-C30 v3.0 score, most symptoms improved after 225 Ac-DOTATATE treatment, with only diarrhea showing no improvement. Grade III/IV hematological, kidney, and liver toxicities were not observed. The median follow-up time was 14 months (7-22 months), and no deaths were reported.

This initial study suggests that 225 Ac-DOTATATE is a potentially promising option for treating NENs with elevated SSTR expression, with an acceptable toxicity profile and well-tolerated adverse effects.

Astatine-211 (211At) has emerged as a promising radionuclide for targeted alpha therapy of cancer by virtue of its favorable nuclear properties. However, the limited in vivo stability of 211At-labeled radiopharmaceuticals remains a major challenge. This review provides a comprehensive overview of the current strategies for 211At radiolabeling, including nucleophilic and electrophilic substitution reactions, as well as the recent advances in the development of novel bifunctional coupling agents and labeling approaches to enhance the stability of 211At-labeled compounds. The preclinical and clinical applications of 211At-labeled radiopharmaceuticals, including small molecules, peptides, and antibodies, are also discussed. Looking forward, the identification of new molecular targets, the optimization of 211At production and quality control methods, and the continued evaluation of 211At-labeled radiopharmaceuticals in preclinical and clinical settings will be the key to realizing the full potential of 211At-based targeted alpha therapy. With the growing interest and investment in this field, 211At-labeled radiopharmaceuticals are poised to play an increasingly important role in future cancer treatment.

This paper aims to address the latest findings in neuroendocrine tumor (NET) theranostics, focusing on new evidence and future directions of combined diagnosis with positron emission tomography (PET) and treatment with peptide receptor radionuclide therapy (PRRT).

Following NETTER-1 trial, PRRT with [177Lu]Lu-DOTATATE was approved by FDA and EMA and is routinely employed in advanced G1 and G2 SST (somatostatin receptor)-expressing NET. Different approaches have been proposed so far to improve the PRRT therapeutic index, encompassing re-treatment protocols, combinations with other therapies and novel indications. Molecular imaging holds a potential added value in characterizing disease biology and heterogeneity using different radiopharmaceuticals (e.g., SST and FDG) and may provide predictive and prognostic parameters. Response assessment criteria are still an unmet need and new theranostic pairs showed preliminary encouraging results. PRRT for NET has become a paradigm of modern theranostics. PRRT holds a favorable toxicity profile, and it is associated with a prolonged time to progression, reduction of symptoms, and improved patients' quality of life. In light of further optimization, different new strategies have been investigated, along with the development of new radiopharmaceuticals.

Radiopharmaceutical therapy has emerged as a promising approach for the treatment of various cancers. The exploration of novel targets such as tumor-specific antigens, overexpressed receptors, and intracellular biomolecules using antibodies, peptides, or small molecules has expanded the scope of radiopharmaceutical therapy, enabling precise and effective cancer treatment for an increasing number of tumor types. Alpha emitters, characterized by their high linear energy transfer and short path length, offer unique advantages in targeted therapy due to their potent cytotoxicity against cancer cells while sparing healthy tissues. This article reviews recent advancements in identifying novel targets for radiopharmaceutical therapy and applications in utilizing α-emitters for targeted treatment.

Theranostics with radioligands (radiotheranostics) has played a pivotal role in oncology. Radiotheranostics explores the molecular targets expressed on tumor cells to target them for imaging and therapy. In this way, radiotheranostics entails non-invasive demonstration of the in vivo expression of a molecular target of interest through imaging followed by the administration of therapeutic radioligand targeting the tumor-expressed molecular target. Therefore, radiotheranostics ensures that only patients with a high likelihood of response are treated with a particular radiotheranostic agent, ensuring the delivery of personalized care to cancer patients. Within the last decades, a couple of radiotheranostics agents, including Lutetium-177 DOTATATE (177Lu-DOTATATE) and Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA), were shown to prolong the survival of cancer patients compared to the current standard of care leading to the regulatory approval of these agents for routine use in oncology care. This recent string of successful approvals has broadened the interest in the development of different radiotheranostic agents and their investigation for clinical translation. In this work, we present an updated appraisal of the literature, reviewing the recent advances in the use of established radiotheranostic agents such as radioiodine for differentiated thyroid carcinoma and Iodine-131-labeled meta-iodobenzylguanidine therapy of tumors of the sympathoadrenal axis as well as the recently approved 177Lu-DOTATATE and 177Lu-PSMA for differentiated neuroendocrine tumors and advanced prostate cancer, respectively. We also discuss the radiotheranostic agents that have been comprehensively characterized in preclinical studies and have shown some clinical evidence supporting their safety and efficacy, especially those targeting fibroblast activation protein (FAP) and chemokine receptor 4 (CXCR4) and those still being investigated in preclinical studies such as those targeting poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor 2.

Radiotheranostics utilizes a set of radioligands incorporating diagnostic or therapeutic radionuclides to achieve both diagnosis and therapy. Imaging probes using diagnostic radionuclides have been used for systemic cancer imaging. Integration of therapeutic radionuclides into the imaging probes serves as potent agents for radionuclide therapy. Among them, targeted alpha therapy (TAT) is a promising next-generation cancer therapy. The α-particles emitted by the radioligands used in TAT result in a high linear energy transfer over a short range, inducing substantial damage to nearby cells surrounding the binding site. Therefore, the key to successful cancer treatment with minimal side effects by TAT depends on the selective delivery of radioligands to their targets. Recently, TAT agents targeting biomolecules highly expressed in various cancer cells, such as sodium/iodide symporter, norepinephrine transporter, somatostatin receptor, αvβ3 integrin, prostate-specific membrane antigen, fibroblast-activation protein, and human epidermal growth factor receptor 2 have been developed and have made remarkable progress toward clinical application. In this review, we focus on two radionuclides, 225Ac and 211At, which are expected to have a wide range of applications in TAT. We also introduce recent fundamental and clinical studies of radiopharmaceuticals labeled with these radionuclides.

This review article explores the evolving landscape of Molecular Radiotherapy (MRT), emphasizing Peptide Receptor Radionuclide Therapy (PRRT) for neuroendocrine tumours (NETs). The primary focus is on the transition from β-emitting radiopharmaceuticals to α-emitting agents in PRRT, offering a critical analysis of the radiobiological basis, clinical applications, and ongoing developments in Targeted Alpha Therapy (TAT). Through an extensive literature review, the article delves into the mechanisms and effectiveness of PRRT in targeting somatostatin subtype 2 receptors, highlighting both its successes and limitations. The discussion extends to the emerging paradigm of TAT, underlining its higher potency and specificity with α-particle emissions, which promise enhanced therapeutic efficacy and reduced toxicity. The review critically evaluates preclinical and clinical data, emphasizing the need for standardised dosimetry and a deeper understanding of the dose-response relationship in TAT. The review concludes by underscoring the significant potential of TAT in treating SSTR2-overexpressing cancers, especially in patients refractory to β-PRRT, while also acknowledging the current challenges and the necessity for further research to optimize treatment protocols.

The lead-203 (203Pb)/lead-212 (212Pb) elementally identical radionuclide pair has gained significant interest in the field of image-guided targeted alpha-particle therapy for cancer. Emerging evidence suggests that 212Pb-labeled peptide-based radiopharmaceuticals targeting somatostatin receptor subtype 2 (SSTR2) may provide improved effectiveness compared to beta-particle-based therapies for neuroendocrine tumors (NETs). This study aims to improve the performance of SSTR2-targeted radionuclide imaging and therapy through structural modifications to Tyr3-octreotide (TOC)-based radiopharmaceuticals.

New SSTR2-targeted peptides were designed and synthesized with the goal of optimizing the incorporation of Pb isotopes through the use of a modified cyclization technique; the introduction of a Pb-specific chelator (PSC); and the insertion of polyethylene glycol (PEG) linkers. The binding affinity of the peptides and the cellular uptake of 203Pb-labeled peptides were evaluated using pancreatic AR42J (SSTR2+) tumor cells and the biodistribution and imaging of the 203Pb-labeled peptides were assessed in an AR42J tumor xenograft mouse model. A lead peptide was identified (i.e., PSC-PEG2-TOC), which was then further evaluated for efficacy in 212Pb therapy studies.

The lead radiopeptide drug conjugate (RPDC) - [203Pb]Pb-PSC-PEG2-TOC - significantly improved the tumor-targeting properties, including receptor binding and tumor accumulation and retention as compared to [203Pb]Pb-DOTA0-Tyr3-octreotide (DOTATOC). Additionally, the modified RPDC exhibited faster renal clearance than the DOTATOC counterpart. These advantageous characteristics of [212Pb]Pb-PSC-PEG2-TOC resulted in a dose-dependent therapeutic effect with minimal signs of toxicity in the AR42J xenograft model. Fractionated administrations of 3.7 MBq [212Pb]Pb-PSC-PEG2-TOC over three doses further improved anti-tumor effectiveness, resulting in 80% survival (70% complete response) over 120 days in the mouse model.

Structural modifications to chelator and linker compositions improved tumor targeting and pharmacokinetics (PK) of 203/212Pb peptide-based radiopharmaceuticals for NET theranostics. These findings suggest that PSC-PEG2-TOC is a promising candidate for Pb-based targeted radionuclide therapy for NETs and other types of cancers that express SSTR2.

Eighty percent of colorectal cancers (CRCs) overexpress epidermal growth factor receptor (EGFR). Kirsten rat sarcoma viral oncogene (KRAS) mutations are present in 40% of CRCs and drive de novo resistance to anti-EGFR drugs. BRAF oncogene is mutated in 7%-10% of CRCs, with even worse prognosis. We have evaluated the effectiveness of [225Ac]Ac-macropa-nimotuzumab in KRAS mutant and in KRAS wild-type and BRAFV600E mutant EGFR-positive CRC cells in vitro and in vivo. Anti-CD20 [225Ac]Ac-macropa-rituximab was developed and used as a nonspecific radioimmunoconjugate. Methods: Anti-EGFR antibody nimotuzumab was radiolabeled with 225Ac via an 18-membered macrocyclic chelator p-SCN-macropa. The immunoconjugate was characterized using flow cytometry, radioligand binding assay, and high-performance liquid chromatography, and internalization was studied using live-cell imaging. In vitro cytotoxicity was evaluated in 2-dimensional monolayer EGFR-positive KRAS mutant DLD-1, SW620, and SNU-C2B; in KRAS wild-type and BRAFV600E mutant HT-29 CRC cell lines; and in 3-dimensional spheroids. Dosimetry was studied in healthy mice. The in vivo efficacy of [225Ac]Ac-macropa-nimotuzumab was evaluated in mice bearing DLD-1, SW620, and HT-29 xenografts after treatment with 3 doses of 13 kBq/dose administered 10 d apart. Results: In all cell lines, in vitro studies showed enhanced cytotoxicity of [225Ac]Ac-macropa-nimotuzumab compared with nimotuzumab and controls. The inhibitory concentration of 50% in the DLD-1 cell line was 1.8 nM for [225Ac]Ac-macropa-nimotuzumab versus 84.1 nM for nimotuzumab. Similarly, the inhibitory concentration of 50% was up to 79-fold lower for [225Ac]Ac-macropa-nimotuzumab than for nimotuzumab in KRAS mutant SNU-C2B and SW620 and in KRAS wild-type and BRAFV600E mutant HT-29 CRC cell lines. A similar trend was observed for 3-dimensional spheroids. Internalization peaked 24-48 h after incubation and depended on EGFR expression. In the [225Ac]Ac-macropa-nimotuzumab group, 3 of 7 mice bearing DLD-1 tumors had complete remission. Median survival was 40 and 34 d for mice treated with phosphate-buffered saline and [225Ac]Ac-macropa-rituximab (control), respectively, whereas it was not reached for the [225Ac]Ac-macropa-nimotuzumab group (>90 d). Similarly, median survival of mice bearing HT-29 xenografts was 16 and 12.5 d for those treated with [225Ac]Ac-macropa-rituximab and phosphate-buffered saline, respectively, and was not reached for those treated with [225Ac]Ac-macropa-nimotuzumab (>90 d). One of 7 mice bearing HT-29 xenografts and treated using [225Ac]Ac-macropa-nimotuzumab had complete remission. Compared with untreated mice, [225Ac]Ac-macropa-nimotuzumab more than doubled (16 vs. 41 d) the median survival of mice bearing SW620 xenografts. Conclusion: [225Ac]Ac-macropa-nimotuzumab is effective against KRAS mutant and BRAFV600E mutant CRC models.

Radiopharmaceuticals play a vital role in cancer therapy. The carrier of radiopharmaceuticals can precisely locate and guide radionuclides to the target, where radionuclides kill surrounding tumor cells. Effective application of radiopharmaceuticals depends on the selection of an appropriate carrier. Herein, different types of carriers of radiopharmaceuticals and the characteristics are briefly described. Subsequently, we review radiolabeled monoclonal antibodies (mAbs) and their derivatives, and novel strategies of radiolabeled mAbs and their derivatives in the treatment of lymphoma and colorectal cancer. Furthermore, this review outlines radiolabeled peptides, and novel strategies of radiolabeled peptides in the treatment of neuroendocrine neoplasms, prostate cancer, and gliomas. The emphasis is given to heterodimers, bicyclic peptides, and peptide-modified nanoparticles. Last, the latest developments and applications of radiolabeled nucleic acids and small molecules in cancer therapy are discussed. Thus, this review will contribute to a better understanding of the carrier of radiopharmaceuticals and the application in cancer therapy.

Radiopharmaceutical therapies (RPTs) are gaining increased interest with the recent emergence of novel safe and effective theranostic agents, improving outcomes for thousands of patients. The term theranostics refers to the use of diagnostic and therapeutic agents that share the same molecular target; a major step toward precision medicine, especially for oncologic applications. The authors dissect the fundamentals of theranostics in nuclear medicine. First, they explain the radioactive decay schemes and the characteristics of emitted electromagnetic radiation used for imaging, as well as particles used for therapeutic purposes, followed by the interaction of the different types of radiation with tissue. These concepts directly apply to clinical RPTs and play a major role in the efficacy and toxicity profile of different radiopharmaceutical agents. Personalized dosimetry is a powerful tool that can help estimate patient-specific absorbed doses, in tumors as well as normal organs. Dosimetry in RPT is an area of active investigation, as most of what we know about the relationship between delivered dose and tissue damage is extrapolated from external-beam radiation therapy; more research is needed to understand this relationship as it pertains to RPTs. Tumor heterogeneity is increasingly recognized as an important prognostic factor. Novel molecular imaging agents, often in combination with fluorine 18-fluorodeoxyglucose, are crucial for assessment of target expression in the tumor and potential hypermetabolic disease that may lack the molecular target expression. ©RSNA, 2023 Test Your Knowledge questions are available in the supplemental material.

PET/CT and radioisotope therapy are diagnostic and therapeutic arms of Nuclear Medicine, respectively. With the emergence of better technology, PET/CT has become an accessible modality. Diagnostic tracers exploring disease-specific targets has led the clinicians to look beyond FDG PET. Moreover, with the emergence of theranostic pairs of radiopharmaceuticals, radioisotope therapy is gradually making it's way into treatment algorithm of common cancers in India. We therefore would like to discuss in detail the updates in PET/CT imaging and radionuclide therapy and generate a consensus-driven evidence based document which would guide the practitioners of Oncology.

The high energy of α emitters, and the strong linear energy transfer that goes along with it, lead to very efficient cell killing through DNA damage. Moreover, the degree of oxygenation and the cell cycle state have no impact on these effects. Therefore, α radioisotopes can offer a treatment choice to individuals who are not responding to β- or gamma-radiation therapy or chemotherapy drugs. Only a few α-particle emitters are suitable for targeted alpha therapy (TAT) and clinical applications. The majority of available clinical research involves 225Ac and its daughter nuclide 213Bi. Additionally, the 225Ac disintegration cascade generates γ decays that can be used in single-photon emission computed tomography (SPECT) imaging, expanding the potential theranostic applications in nuclear medicine. Despite the growing interest in applying 225Ac, the restricted global accessibility of this radioisotope makes it difficult to conduct extensive clinical trials for many radiopharmaceutical candidates. To boost the availability of 225Ac, along with its clinical and potential theranostic applications, this review attempts to highlight the fundamental physical properties of this α-particle-emitting isotope, as well as its existing and possible production methods.

To select the most suitable chelate for 225 Ac radiolabeling of the anti-FZD10 antibody OTSA101, we directly compared three chelates: S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2,2',2″-(10-(1-carboxy-4-((4-isothiocyanatobenzyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (p-SCN-Bn-DOTAGA), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DO3A-NHS-ester). We evaluated the binding affinity of the chelate-conjugated OTSA101 antibodies, as well as the labeling efficiency and stability in murine serum of 225 Ac-labeled OTSA101 as in vitro properties. The biodistribution, intratumoral distribution, absorbed doses, and therapeutic effects of the chelate-conjugated OTSA101 antibodies were assessed in the synovial sarcoma mouse model SYO-1. Of the three conjugates, DOTAGA conjugation had the smallest impact on the binding affinity (p < 0.01). The labeling efficiencies of DOTAGA-OTSA101 and DO3A-OTSA101 were 1.8-fold higher than that of DOTA-OTSA101 (p < 0.01). The stabilities were similar between 225 Ac-labeled DOTA-OTSA101, DOTAGA-OTSA101, and DO3A-OTSA101in serum at 37 and 4°C. The dosimetric analysis based on the biodistribution revealed significantly higher tumor-absorbed doses by 225 Ac-labeled DOTA-OTSA101 and DOTAGA-OTSA101 compared with 225 Ac-DO3A-OTSA101 (p < 0.05). 225 Ac-DOTAGA-OTSA101 exhibited the highest tumor-to-bone marrow ratio, with bone marrow being the dose-limiting tissue. The therapeutic and adverse effects were not significantly different between the three conjugates. Our findings indicate that among the three evaluated chelates, DOTAGA appears to be the most promising chelate to produce 225 Ac-labeled OTSA101 with high binding affinity and high radiochemical yields while providing high absorbed doses to tumors and limited absorbed doses to bone marrow.

Overexpression of somatostatin receptors (SSTR), particularly SSTR2, is found in gastroenteropancreatic neuroendocrine tumors (GEP-NET), and subsets of other solid tumors such as small-cell lung cancer (SCLC). SCLC accounts for approximately 13% to 15% of lung cancer and lacks effective therapeutic options. IHC analysis indicates that up to 50% of SCLC tumors are SSTR2-positive, with a substantial subset showing high and homogenous expression. Peptide receptor radionuclide therapy with radiolabeled somatostatin analogue, Lu-177 DOTATATE, has been approved for GEP-NETs. Different strategies aimed at improving outcomes, such as the use of alpha-emitting radioisotopes, are currently being investigated. RYZ101 (Ac-225 DOTATATE) is comprised of the alpha-emitting radioisotope actinium-225, chemical chelator DOTA, and octreotate (TATE), a somatostatin analogue. In the cell-based competitive radioligand binding assay, RAYZ-10001-La (lanthanum surrogate for RYZ101) showed high binding affinity (Ki = 0.057 nmol/L) to human SSTR2 and >600-fold selectivity against other SSTR subtypes. RAYZ-10001-La exhibited efficient internalization to SSTR2-positive cells. In multiple SSTR2-expressing SCLC xenograft models, single-dose intravenous RYZ101 3 μCi (0.111 MBq) or 4 μCi (0.148 MBq) significantly inhibited tumor growth, with deeper responses, including sustained regression, observed in the models with higher SSTR2 levels. The antitumor effect was further enhanced when RYZ101 was combined with carboplatin and etoposide at clinically relevant doses. In summary, RYZ101 is a highly potent, alpha-emitting radiopharmaceutical agent, and preclinical data demonstrate the potential of RYZ101 for the treatment of patients with SSTR-positive cancers.

In this study we determined the dose-independent relative biological effectiveness (RBE2) of bone marrow for an anti-HER2/neu antibody labeled with the alpha-particle emitter actinium 225 (225Ac). Hematologic toxicity is often a consequence of radiopharmaceutical therapy (RPT) administration, and dosimetric guidance to the bone marrow is required to limit toxicity.

Female neu/N transgenic mice (MMTV-neu) were intravenously injected with 0 to 16.65 kBq of the alpha-particle emitter labeled antibody, 225Ac-DOTA-7.16.4, and euthanized at 1 to 9 days after treatment. Complete blood counts were performed. Femurs and tibias were collected, and bone marrow was isolated from 1 femur and tibia and counted for radioactivity. Contralateral intact femurs were fixed, decalcified, and assessed by histology. Marrow cellularity was the biologic endpoint selected for RBE2 determination. For the reference radiation, both femurs of the mice were photon irradiated with 0 to 5 Gy using a small animal radiation research platform.

Response as measured by cellularity for the alpha-particle emitter RPT (αRPT) RPT and the external beam radiation therapy were linear and linear quadratic, respectively, as a function of absorbed dose. The resulting dose-independent RBE2 for bone marrow was 6.

As αRPT gains prominence, preclinical studies evaluating RBE in vivo will be important in relating to human experience with beta-particle emitter RPT. Such normal tissue RBE evaluations will help mitigate unexpected toxicity in αRPT.

In nuclear medicine, cancers that cannot be cured or can only be treated partially by traditional techniques like surgery or chemotherapy are killed by ionizing radiation as a form of therapeutic treatment. Actinium-225 is an alpha-emitting radionuclide that is highly encouraging as a therapeutic approach and more promising for targeted alpha therapy (TAT). Actinium-225 is the best candidate for tumor cells treatment and has physical characteristics such as high (LET) linear energy transfer (150 keV per μm), half-life (t1/2  = 9.92d), and short ranges (400-100 μm) which prevent the damage of normal healthy tissues. The introduction of various new radiopharmaceuticals and radioisotopes has significantly assisted the advancement of nuclear medicine. Ac-225 radiopharmaceuticals continuously demonstrate their potential as targeted alpha therapeutics. 225 Ac-labeled radiopharmaceuticals have confirmed their importance in medical and clinical areas by introducing [225 Ac]Ac-PSMA-617, [225 Ac]Ac-DOTATOC, [225 Ac]Ac-DOTA-substance-P, reported significantly improved response in patients with prostate cancer, neuroendocrine, and glioma, respectively. The development of these radiopharmaceuticals required a suitable buffer, incubation time, optimal pH, and reaction temperature. There is a growing need to standardize quality control (QC) testing techniques such as radiochemical purity (RCP). This review aims to summarize the development of the Ac-225 labeled compounds and biomolecules. The current state of their reported resulting clinical applications is also summarized as well.

Molecular changes in malignant tissue can lead to an increase in the expression levels of various proteins or receptors that can be used to target the disease. In oncology, diagnostic imaging and radiotherapy of tumors is possible by attaching an appropriate radionuclide to molecules that selectively bind to these target proteins. The term "theranostics" describes the use of a diagnostic tool to predict the efficacy of a therapeutic option. Molecules radiolabeled with γ-emitting or β+-emitting radionuclides can be used for diagnostic imaging using single photon emission computed tomography or positron emission tomography. Radionuclide therapy of disease sites is possible with either α-, β-, or Auger-emitting radionuclides that induce irreversible damage to DNA. This Focus Review centers on the chemistry of theranostic approaches using metal radionuclides for imaging and therapy. The use of tracers that contain β+-emitting gallium-68 and β-emitting lutetium-177 will be discussed in the context of agents in clinical use for the diagnostic imaging and therapy of neuroendocrine tumors and prostate cancer. A particular emphasis is then placed on the chemistry involved in the development of theranostic approaches that use copper-64 for imaging and copper-67 for therapy with functionalized sarcophagine cage amine ligands. Targeted therapy with radionuclides that emit α particles has potential to be of particular use in late-stage disease where there are limited options, and the role of actinium-225 and lead-212 in this area is also discussed. Finally, we highlight the challenges that impede further adoption of radiotheranostic concepts while highlighting exciting opportunities and prospects.