Chemical and radiochemical considerations in radiolabeling with α-emitting radionuclides

A review of chemical and radiochemical factors that must be considered when radiolabeling targeting agents with radionuclides is presented. The review discusses factors that are important in choice of radionuclide and choice of chelation or bonding reagents to use in the development of an α-emitting radiopharmaceutical. Chemical parameters, such as physical properties and pendant groups for radiolabeling, are reviewed. A major portion of the review outlines the development of chelates and labeling conditions for radiometals, and application of these reagents/conditions to radiometals. Acyclic and macrocyclic chelates containing amine and carboxylic acid coordination groups are highlighted, with examples of bifunctional chelates for biomolecule conjugation. Information is presented on over 60 radiometal-binding chelates. 211At radiolabeling is separated from that of radiometals, and the various reagents used for radiolabeling have been reviewed. Although not all 211At-labeling reagents are reviewed (due to another recent review), nearly 50 reagents studied in the development of pendant groups for labeling with 211At are described. The review also discusses how therapeutic doses of α-emitting radiopharmaceuticals can be affected by the radionuclide used and how radiation damage to the radiopharmaceutical can be minimized.     

Validation of the 3-variable prognostic score (3-PS) in mCRPC patients treated with 223Radium-dichloride: a national multicenter study

Annals of Nuclear Medicine - Radium-223 (223Ra) has been approved for treatment in patients with metastatic castration-resistant prostatic cancer (mCRPC) and bone metastasis. This α-emitting...     

Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice.

The bone-seeking property and the potential exposure of red marrow by the alpha-particle emitter (223)Ra (half-life, 11.43 d) were compared with those of the beta-emitter (89)Sr (half-life, 50.53 d). METHODS: The biodistributions of (223)Ra and (89)Sr were studied in mice. Tissue uptake was determined at 1 h, 6 h, 1 d, 3 d, and 14 d after intravenous administration. Radiation absorbed doses were calculated for soft tissues and for bone. Multicellular-level doses were estimated for bone marrow cavities. RESULTS: Both (89)Sr and (223)Ra selectively concentrated on bone surfaces relative to soft tissues. The measured bone uptake of (223)Ra was slightly higher than that of (89)Sr. At 24 h, the femur uptake of (223)Ra was 40.1% +/- 7.7% of the administered activity per gram of tissue. The uptake in spleen and most other soft tissues was higher for (223)Ra than for (89)Sr. Although predominant clearance of (223)Ra was observed from the soft tissues within the first 24 h, the bone uptake of (223)Ra, which was not significantly different from maximum after only 1 h, was not significantly reduced during the 14 d. Furthermore, little redistribution of (223)Ra daughter products away from bone was found (2% at 6 h and less than 1% at 3 d). Estimates of dose to marrow cavities showed that the (223)Ra alpha-emitter might have a marrow-sparing advantage compared with beta-emitters for targeting osteoid surfaces because the short-range alpha-particles irradiate a significantly lower fraction of the marrow volumes. At the same time, the bone surfaces will receive a therapeutically effective radiation dose. CONCLUSION: The results of this study indicate that (223)Ra is a promising candidate for high-linear-energy transfer alpha-particle irradiation of cancer cells on bone surfaces. (223)Ra can, together with its daughter radionuclides, deliver an intense and highly localized radiation dose to the bone surfaces with substantially less irradiation of healthy bone marrow compared with standard bone-seeking beta-emitters.     

A method to predict response of cell populations to cocktails of chemotherapeutics and radiopharmaceuticals: Validation with daunomycin, doxorubicin, and the alpha particle emitter (210)Po

There is considerable interest in the use of α-emitting radionuclides in radioimmunotherapy. However, the high toxicity of α-emitting radionuclides often does not permit administration of high activities for fear of normal tissue toxicity. Accordingly, targeting procedures need to be optimized for improved tumor control and minimized normal tissue toxicity. To guide design of effective cocktails of α-emitting radiopharmaceuticals and chemotherapy drugs, approaches that can predict biological response of a cell population on a cell-by-cell basis are needed.MethodsCells were concomitantly treated with the α-particle emitting radiochemical ²¹⁰Po-citrate and daunomycin, or with ²¹⁰Po-citrate and doxorubicin. The responses of the treated cell populations were measured with a colony forming assay. The nonuniform cellular incorporation of the radiochemical and drugs was determined simultaneously on a cell-by-cell basis using flow cytometry. Monte Carlo methods were used to simulate cell survival on the basis of individual cell incorporation of each cytotoxic agent and validated by direct comparison with the experimental clonogenic cell survival.ResultsBoth daunomycin and doxorubicin enhanced the toxicity of the α-particles with a magnitude greater than expected based on single-agent toxicities. Cell survival obtained by Monte Carlo simulation was in good agreement with clonogenic cell survival for the combination treatments.ConclusionFlow cytometry assisted Monte Carlo simulations can be used to predict toxicity of cocktails of α-emitting radiopharmaceuticals and chemotherapy drugs in a manner that takes into account the effects of nonuniform distributions of agents within cell populations.     

Sterically stabilized liposomes as a carrier for alpha-emitting radium and actinium radionuclides

The alpha-particle emitting radionuclides (223)Ra (t(1/2) = 11.4 d), (224)Ra (t(1/2) = 3.6 d), and (225)Ac(t(1/2) = 10.0 d) may have a broad application in targeted radiotherapy provided that they could be linked to vehicles with tumor affinity. The potential usefulness of liposomes as carriers was studied in the present work. Radium and actinium radionuclides could be loaded in good yields into sterically stabilized liposomes. Subsequent coating of the liposomes with a folate-F(ab')(2) construct yielded a product with affinity towards tumor cells expressing folate receptors. Radionuclide loaded liposomes showed excellent stability in serum in vitro.     

Cellular dose conversion factors for alpha-particle--emitting radionuclides of interest in radionuclide therapy.

alpha-Particle--emitting radionuclides are of increasing interest in radionuclide therapy. The decay scheme of alpha-emitting radionuclides typically includes a chain of unstable progeny. It is generally assumed that alpha-particle emission by the parent radionuclide will break the chemical bond with its carrier molecule and that the resulting daughter atom will no longer be associated with the carrier molecule. If the daughter is very short lived, it will not have enough time to be carried any significant distance from the site of parent decay and a cellular, absorbed dose estimate must consider the energy deposited by the daughter as well as the parent. Depending on the site of parent decay and the expected removal rate of daughter atoms from this site, the contribution of emissions from longer-lived daughters may also be warranted. In this study, dose conversion factors (DCFs) for cellular dimensions that incorporate the fate of daughter radionuclides were derived for (225)Ac, (213)Bi, (211)At, and (223)Ra, the alpha-particle--emitting radionuclides of interest in radionuclide therapy. METHODS: The dose contribution of daughter radionuclides at the site of parent decay was made dependent on a cutoff time parameter, which was used to estimate the fraction of daughter decays expected at the site of parent decay. Previously tabulated S values (cell-surface to nucleus and cell-surface to cell) for each daughter in the decay scheme were scaled by this fraction and a sum over all daughters was performed to yield a cutoff time--dependent set of corresponding DCF values for each radionuclide. RESULTS: DCF values for the absorbed dose to the nuclear or cellular volume from cell-surface decays are presented as a function of the cutoff time for 4 different cellular and nuclear dimensions. CONCLUSION: In contrast to the cellular S values that account only for parent decay, the DCF values provided in this study make it possible to easily include the contribution of daughter decays in cellular alpha-particle emitter dose calculations.     

A rapid method for alpha-spectrometric analysis of radium isotopes in natural waters using ion-selective membrane technology.

An alpha-spectrometric method for the rapid determination of radium isotopes (223Ra, 224Ra and 226Ra) in environmental samples is presented. Using Empore Radium Rad Disks complete separation of the target radionuclides is achieved. The high selectivity of these Rad Disks allows the straightforward use of 225Ra as yield tracer. Chemical yield is up to 92 +/- 9%. The chemical procedure can be accomplished within 5h. Alpha-sources show energy resolution in the range of typically 26-40 keV (FWHM). Despite minimal thickness of the sources no significant radon (Rn) losses can be observed.     

Optimisation study of α-cyclotron production of At-211/Po-211g for high-LET metabolic radiotherapy purposes

The production of no-carrier-added (NCA) α-emitter ²¹¹At/^211gPo radionuclides for high-LET targeted radiotherapy and immunoradiotherapy, through the ²⁰⁹Bi(α,2n) reaction, together with the required wet radiochemistry and radioanalytical quality controls carried out at LASA is described, through dedicated irradiation experiments at the MC-40 cyclotron of JRC-Ispra. The amount of both the γ-emitter ²¹⁰At and its long half-lived α-emitting daughter ²¹⁰Po is optimised and minimised by appropriate choice of energy and energy loss of α particle beam. The measured excitation functions for production of the main radioisotopic impurity ²¹⁰At→²¹⁰Po are compared with theoretical predictions from model calculations performed at ENEA.     

Astatine-211: production and availability

The 7.2-h half life radiohalogen (211)At offers many potential advantages for targeted α-particle therapy; however, its use for this purpose is constrained by its limited availability. Astatine-211 can be produced in reasonable yield from natural bismuth targets via the (209)Bi(α,2n)(211)At nuclear reaction utilizing straightforward methods. There is some debate as to the best incident α-particle energy for maximizing 211At production while minimizing production of (210)At, which is problematic because of its 138.4-day half life α-particle emitting daughter, (210)Po. The intrinsic cost for producing (211)At is reasonably modest and comparable to that of commercially available (123)I. The major impediment to (211)At availability is attributed to the need for a medium energy α-particle beam for its production. On the other hand, there are about 30 cyclotrons in the world that have the beam characteristics required for (211)At production.     

Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6.

alpha-Particle-emitting radionuclides, such as (211)At, with a 7.2-h half-life, may be optimally suited for the molecularly targeted radiotherapy of strategically sensitive tumor sites, such as those in the central nervous system. Because of the much shorter range and more potent cytotoxicity of alpha-particles than of beta-particles, (211)At-labeled agents may be ideal for the eradication of tumor cells remaining after surgical debulking of malignant brain tumors. The main goal of this study was to investigate the feasibility and safety of this approach in patients with recurrent malignant brain tumors. METHODS: Chimeric antitenascin monoclonal antibody 81C6 (ch81C6) (10 mg) was labeled with 71-347 MBq of (211)At by use of N-succinimidyl 3-[(211)At]astatobenzoate. Eighteen patients were treated with (211)At-labeled ch81C6 ((211)At-ch81C6) administered into a surgically created resection cavity (SCRC) and then with salvage chemotherapy. Serial gamma-camera imaging and blood sampling over 24 h were performed. RESULTS: A total of 96.7% +/- 3.6% (mean +/- SD) of (211)At decays occurred in the SCRC, and the mean blood-pool percentage injected dose was < or = 0.3. No patient experienced dose-limiting toxicity, and the maximum tolerated dose was not identified. Six patients experienced grade 2 neurotoxicity within 6 wk of (211)At-ch81C6 administration; this neurotoxicity resolved fully in all but 1 patient. No toxicities of grade 3 or higher were attributable to the treatment. No patient required repeat surgery for radionecrosis. The median survival times for all patients, those with glioblastoma multiforme, and those with anaplastic astrocytoma or oligodendroglioma were 54, 52, and 116 wk, respectively. CONCLUSION: This study provides proof of concept for regional targeted radiotherapy with (211)At-labeled molecules in oncology. Specifically, the regional administration of (211)At-ch81C6 is feasible, safe, and associated with a promising antitumor benefit in patients with malignant central nervous system tumors.     

Radioimmunotherapy with alpha-emitting nuclides

This review discusses the application of alpha particle-emitting radionuclides in targeted radioimmunotherapy. It will outline the production and chemistry of astatine-211, bismuth-212, lead-212, actinium-225, bismuth-213, fermium-255, radium-223 and terbium-149, which at present are the most promising alpha-emitting isotopes available for human clinical use. The selective cytotoxicity offered by alpha particle-emitting radioimmunoconstructs is due to the high linear energy transfer and short particle path length of these radionuclides. Based upon the pharmacokinetics of alpha particle-emitting radioimmunoconstructs, both stochastic and conventional dosimetric methodology is discussed, as is the preclinical and initial clinical use of these radionuclides conjugated to monoclonal antibodies for the treatment of human neoplasia.     

Computational modeling of radiobiological effects in bone metastases for different radionuclides

Purpose: Computational simulation is a simple and practical way to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aimed to evaluate and compare cellular effects modelled for different radioisotopes currently in use or under research for treatment of bone metastases using computational methods.

Methods: Computational models were used to estimate the radiation-induced cellular effects (Virtual Cell Radiobiology algorithm) post-irradiation with selected particles emitted by Strontium-89 (⁸⁹Sr), Samarium-153 (¹⁵³Sm), Lutetium-177 (¹⁷⁷Lu), and Radium-223 (²²³Ra).

Results: Cellular kinetics post-irradiation using ⁸⁹Sr β^? particles, ¹⁵³Sm β^??particles, ¹⁷⁷Lu β^??particles and ²²³Ra α particles showed that the cell response was dose- and radionuclide-dependent. ¹⁷⁷Lu beta minus particles and, in particular, ²²³Ra alpha particles, yielded the lowest survival fraction of all investigated particles.

Conclusions: ²²³Ra alpha particles induced the highest cell death of all investigated particles on metastatic prostate cells in comparison to irradiation with β^??radionuclides, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice. Moreover, the data obtained suggest that the used computational methods might provide some perception about cellular effects following irradiation with different radionuclides.     

Optimisation study of alpha-cyclotron production of At-211/Po-211g for high-LET metabolic radiotherapy purposes.

The production of no-carrier-added (NCA) alpha-emitter (211)At/(211g)Po radionuclides for high-LET targeted radiotherapy and immunoradiotherapy, through the (209)Bi(alpha,2n) reaction, together with the required wet radiochemistry and radioanalytical quality controls carried out at LASA is described, through dedicated irradiation experiments at the MC-40 cyclotron of JRC-Ispra. The amount of both the gamma-emitter (210)At and its long half-lived alpha-emitting daughter (210)Po is optimised and minimised by appropriate choice of energy and energy loss of alpha particle beam. The measured excitation functions for production of the main radioisotopic impurity (210)At-->(210)Po are compared with theoretical predictions from model calculations performed at ENEA.     

Transport of free 211At and 125I- in thyroid epithelial cells: effects of anion channel blocker 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid on apical efflux and cellular retention

INTRODUCTION: Astatine ((211)At; alpha-emitter; t(1/2)=7.21 h) shares several features with its halogen neighbour iodine. In the present study, we investigated whether 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) can be used to increase the cellular retention time of (211)At and radioiodide in thyroid epithelial cells. METHODS: The transepithelial transport and cellular uptake of (211)At and (125)I(-) were studied simultaneously in porcine thyrocytes cultured in bicameral chambers. The cells were prestimulated with thyroid-stimulating hormone (TSH) or epidermal growth factor (EGF) for 48 h. In addition, the acute effects of DIDS and forskolin were investigated. RESULTS: The transepithelial transport of both radionuclides was stimulated by TSH and down-regulated by EGF. DIDS rapidly reduced the efflux and increased the cellular content of (125)I(-) in control and TSH-stimulated cells, whereas DIDS had no effect on (125)I(-) transport in EGF-treated cells. DIDS blocked the (211)At efflux only in TSH-stimulated cells. Unexpectedly, DIDS caused an accelerated efflux of (211)At in both control and EGF-stimulated cells and, furthermore, reduced the cellular content of (211)At in the EGF-stimulated cultures. DIDS had no effect on the forskolin-induced efflux of the two radionuclides. CONCLUSIONS: The magnitude of thyroidal (211)At uptake and efflux is similar to that of (125)I(-), strongly dependent on the functional activity of the cells. However, (211)At efflux likely involves several permeating mechanisms with different sensitivity to DIDS, which are at least partly not shared by (125)I(-). The results suggest that anion channel blockage is potentially useful to increase the absorbed dose from both (211)At and radioiodine in NIS-expressing tumours.     

Simultaneous determination of Ra and Th nuclides, 238U and 227Ac in uranium mining waters by γ-ray spectrometry

For the investigation of flooding processes in uranium mines, Ra and Th nuclides as well as ²³⁸U and ²²⁷Ac activities in waters were simultaneous analyzed by γ-ray spectrometry. The activities of ²²⁷Ac and ²²⁸Th, not directly determinable by γ-ray spectrometry, can be calculated from two consecutive measurements (≈25 d delay) of the progeny ²²⁷Th and ²²⁴Ra. For the short-lived radionuclides ²³⁴Th, ²²⁷Th, ²²³Ra and ²²⁴Ra a correction of the results to the sampling date is necessary.     

Radiogenic nephropathy

Patient-individual dosimetric analyses are a useful tool in external beam radiotherapy (EBR) to protect patients from side effects such as radiogenic nephropathy. At this point in time, individual dosimetry is not used as a standard in patient treated with radiolabelled antibody fragments or polypeptides. The reasons are a number of problems, which make patient dosimetry more challenging than in EBR. While in EBR, the dose is distributed evenly in the organ and the organ volume can exactly be determined, in internal radiotherapy the tracer is not evenly distributed within the organ leading to a non-uniform dose distribution. In addition, the dose rate of the most commonly used radionuclides is lower than in EBR and the range of their radiation differ, so that the radiobiological effects are differing considerably in comparison to EBR. Conclusion: More complex models have to be used for clinical kidney dosimetry in internal radiotherapy. In this paper, we give a concise overview of the reasons for accumulation of radiotracers in the kidney, the most recent developments in kidney dosimetry, and approaches to reduce the kidney uptake of radiotracers in order to avoid radiogenic nephropathy.     

Comparative cellular catabolism and retention of astatine-, bismuth-, and lead-radiolabeled internalizing monoclonal antibody.

Monoclonal antibodies (mAbs) labeled with alpha-emitting radionuclides such as (211)At, (212)Bi, (213)Bi, and (212)Pb (which decays by beta-emission to its alpha-emitting daughter, (212)Bi) are being evaluated for their potential applications for cancer therapy. The fate of these radionuclides after cells are targeted with mAbs is important in terms of dosimetry and tumor detection. METHODS: In this study, we attached various radionuclides that result in alpha-emissions to T101, a rapidly internalizing anti-CD5 mAb. We then evaluated the catabolism and cellular retention and compared them with those of (125)I- and (111)In-labeled T101. T101 was labeled with (211)At, (125)I, (205,6)Bi, (111)In, and (203)Pb. CD5 antigen-positive cells, peripheral blood mononuclear cells (PBMNC), and MOLT-4 leukemia cells were used. The labeled T101 was incubated with the cells for 1 h at 4 degrees C for surface labeling. Unbound activity was removed and 1 mL medium added. The cells were then incubated at 37 degrees C for 0, 1, 2, 4, 8, and 24 h. The activity on the cell surface that internalized and the activity on the cell surface remaining in the supernatant were determined. The protein in the supernatant was further precipitated by methanol for determining protein-bound and non-protein-bound radioactivity. Sites of internal cellular localization of radioactivity were determined by Percoll gradient centrifugation. RESULTS: All radiolabeled antibodies bound to the cells were internalized rapidly. After internalization, (205,6)Bi, (203)Pb, and (111)In radiolabels were retained in the cell, with little decrease of cell-associated radioactivity. However, (211)At and (125)I were released from cells rapidly ((211)At < (125)I) and most of the radioactivity in the supernatant was in a non-protein-bound form. Intracellular distribution of radioactivity revealed a transit of the radiolabel from the cell surface to the lysosome. The catabolism patterns of MOLT-4 cells and PBMNC were similar. CONCLUSION: (211)At catabolism and release from cells were somewhat similar to that of (125)I, whereas (205,6)Bi and (203)Pb showed prolonged cell retention similar to that of (111)In. These catabolism differences may be important in the selection of alpha-radionuclides for radioimmunotherapy.     

Automated preparation of Re-188 lipiodol for the treatment of hepatocellular carcinoma

The iodinated oil lipiodol is commonly used as a carrier for in situ delivery of drugs or radioactivity to hepatic tumors. Recently, we reported a new kit formulation for high-activity labeling of lipiodol with the β-emitting radionuclide Re-188. Since the whole preparation involves different steps and complex manipulations of high-activity samples, we describe here an automated synthesis module that allows the easy preparation of sterile and pyrogen-free samples of Re-188 lipiodol ready to be administered to the patient. Important advantages include the possibility to incorporate high Re-188 activity into the lipiodol hydrophobic phase and a sharp reduction of radiation exposure of the operator assisting the labelling procedure. Application of this modular reaction system could be also extended to the preparation of other Re-188 radiopharmaceuticals and to compound labelled with different β-emitting therapeutic radionuclides.     

Some microdosmetric data on Astatine-211.

Radionuclides which emit short range, high LET radiations such as alpha and Auger electrons have very promising applications in cancer therapy. Such radionuclides should eventually be incorporated into cell nuclei to achieve high radiotoxic effectiveness. This means that the dose distribution within the cell nucleus at microscopic levels is very important for comparison of the real differences between the radiotoxic effectiveness of different radionuclides. An experimental setup to determine real dose absorption on the microscopic scale is extremely difficult to design. For this reason, calculation procedures for microscopic dose absorption are of special interest for the diagnostic and therapeutic applications of radionuclides which emit short-range and high LET radiations. A specific calculation method for microscopic energy absorptions within the cell nucleus from Auger electrons of 125I was described earlier. In this study, the radiotoxic effectiveness of 211At and 125I has been compared using the data obtained by this calculation method. The data obtained show clearly that the radiotoxicity of the alpha and Auger emitter radionuclide 211At is comparable to that of 125I.     

Targeted alpha therapy: part I

The possibility of pinpointing biological targets, and thereby potentially targeting and eradicating small tumors or even single cancer cells, is a tantalizing concept that has been discussed since the magic-bullet concept was first presented by Paul Erlich in the beginning of the 20th century in connection with his work on tissue staining for histological examinations and the work by Kohler and Milstein on antibody production published in 1975. This concept now seems feasible through the use of highly specific targeting constructs, chemical labeling of radioactive substances to these targeting constructs that results in high specific activities, radioimmunocomplexes with good stability even after injection, and the use of radionuclides emitting alpha( α)-particles having exceedingly high ionizing density and, therefore, a high probability of killing cells along its track in tissue. The short range of the emitted α-particles makes them even more interesting by minimizing unwanted irradiation of normal tissue surrounding the targeted cancer cells of interest, assuming high specificity of the targeting construct and good stability of the chemical bonds between the targeting construct and the α-particle emitter. Targeted Alpha Therapy (TAT), in which an α-particle emitting radionuclide is specifically directed to the biological target, is gaining more attention as new targets, targeting constructs, chemical labeling techniques, and α-particle emitters are, respectively, identified, constructed, developed, and made available. Results and improvements are now being published at an increasing rate and the number of conceivable applications is expanding, especially in the field of cancer treatment. Therefore, it is of utmost importance to provide an overview of the overall progress in the research field of TAT on a regular basis. However, problems such as limited or delayed diffusion of the α-radioimmunocomplex and inhomogeneous activity distributions in the targeted tumors, resulting in inhomogeneous absorbed dose distributions, are challenges that need to be addressed. These challenges need to be overcome before TAT becomes a standard treatment for diseases such as micrometastatic cancer. Hopefully, when enough funding will be provided and, hence, more treatment strategies of TAT will reach the clinical level the importance to conduct controlled, randomized trials with sufficient patient numbers, enabling statistical significance to occur must be emphasized in order to be able to properly compare and evaluate different approaches. In this issue, of the two hot-topic issues for targeted alpha therapy, articles discuss the recent developments in radionuclide availability, biomolecular targeting, labeling chemistry, and dosimetry for the most promising α-particle emitters. In the first article, Zalutsky et al. discuss the possibilities and limitations of using the promising α-particle emitter, 211At, and emphasize the need for funding new cyclotrons and prioritizing beam-times of already existing cyclotrons to improve the availability of 211At. Haddad et al. describe the status of the ARRONAX project through which a number of important nuclear medicine radionuclides will be produced, including some of those suitable for TAT. Relevant targeting constructs and their associated antigens used today and candidates for use in the future are discussed by Olafsen et al. in the third article. The next article, by Scott Wilbur, discusses chemical and radiochemical issues of radiolabeling using α-particle emitting radionuclides, e.g. factors that are important in selecting chelation or bonding reagents during the development of α-particle emitting radiopharmaceuticals. Lindegren at al. continue the discussion of chemical considerations in the following article, but focuses on pre-targeting techniques, which will hopefully enhance both the activity distribution in the targeted tumor and the tumor-to-normal tissue absorbed dose ratio. The two final articles discuss different aspects of the dosimetry related to α-particles. The article by Sgouros et al. discusses how knowledge of the microscopic distribution of α-particle emitters is necessary to perform correct dosimetry, as well as the importance of the translation of activity distributions obtained in pre-clinical studies to the human situation, which requires micro-scale models of the source-target geometry at human dimensions according to the authors. Chouin et al. focus in the following article on the microdosimetry of α-particles. The authors present basic concepts and some applications of the microdosimetry for TAT, and conclude microdosimetry should only be considered when alternative approaches fail to provide an account of a given biological endpoint. The intention of this particular hot-topic issue is to present an up-to-date overview of key areas in the research field of TAT, i.e. radionuclides available, targeting constructs, labeling chemistry, and dosimetry. This issue will hopefully be followed by similar ones jointly produced by contributions from the research community active in the field, of which most researchers are participating in these two particular issues, i.e. Targeted Alpha Therapy - Part I and II.