[en] Full text: Targeted radiotherapy involves the use of a molecular carrier such as a receptor-avid compound or an antibody to deliver a radionuclide to malignant cell populations. This emerging therapeutic strategy has a number of potential advantages that compensate for its relatively complex nature. Compared with conventional external beam radiation treatment, targeted radionuclide therapy offers the prospect of more selectively delivering lethal radiation doses to tumour cells while leaving neighboring normal cells intact. And unlike conceptually similar targeted therapeutics employing toxins or chemotherapeutics as the cytotoxic agent, radionuclides do not require intracellular localization to be effective. Indeed, one of the attractions of radionuclide therapy is the existence of radiation with quite different dimensions of effectiveness, ranging from sub-cellular (Auger electrons) to hundreds of cell diameters (β-particles). One of the attractive features of α-particles for targeted radiotherapy is their intermediate tissue range equivalent to only a few cell diameters. An important consequence of the relatively short range of α-particles is that this characteristic, in combination with their high energy (4-9 MeV for the radionuclides of interest for radionuclide therapy), impart a high linear energy transfer (LET) quality to this radiation. Yttrium-90 emits high energy β-particles that have a mean LET of about 0.2 keV/μm; in comparison, the LET of clinically relevant ?-particle emitters is several orders of magnitude higher, about 100 keV/μm. The radiobiological implications of high LET radiation are perhaps the most compelling rationale for pursuing α-particle emitters for therapy. Of primary importance is the fact that the relative biological effectiveness of high LET radiation is considerably higher than β-particles or standard external beam radiation, and this has been validated experimentally with a variety of radionuclides, carrier molecules and human cancer cell lines. In addition, the conditions under which high-LET radiation is maximally effective are relatively wide-ranging, not being compromised by a lack of oxygen, cell cycle stage or dose rate. Although the potential advantages of α-particle emitters for targeted radiotherapy have been appreciated for many years, translation of this concept into the clinical domain has been slow. Many of the reasons for this are in the realm of radiopharmaceutical chemistry. One problem has been the poor availability of α-particle emitters with real potential for cancer treatment. Another is the need for labeling methods that provide sufficient stability in the in vivo environment to be suitable for patient studies. An important consideration for therapeutic radiopharmaceutical chemistry that is particularly pertinent for α-particle emitters is the potential deleterious effects of radiolysis on labeling chemistry and product stability. Even though more than 100 α-particle emitting radionuclides exist, to date, less than 10 of them have received serious attention for targeted radiotherapy applications. This can be attributed in part to the fact that most α-particle emitters are part of natural decay chains with multiple daughter radionuclides, necessitating the development of strategies that can compensate for the often divergent chemical behaviour of the radioactive parent and daughter. To date, the α-particle emitters that have been utilized for clinical investigations include 45.6- min ²¹³Bi, 7.2-h ²¹¹At, and 11.4-d ²²³Ra, while 61-min ²¹²Bi, 4.2-h ¹⁴⁹Tb and 10-d ²²⁵Ac have been explored in cell culture and animal models of human cancer. A wide variety of molecular carriers have been investigated including monoclonal antibodies, peptides, bone-seeking complexes as well as receptor- and transporter-avid molecules. In this review, the current status of targeted α-particle radiotherapy will be summarized. Among the topics to be presented will be radiolytic effects on l abeling chemistry and heterogeneous dose delivery, two problems that must be solved if targeted radiotherapy with α-particle emitting radionuclides is to become a practical approach for cancer therapy. (author)

[en] One of the key impediments to the use of ²¹¹At is the very well known deleterious effect of high radiation fields caused by its alpha particles on the synthesis of ²¹¹At-labelled radiopharmaceuticals. This is problematic because radiolysis-mediated effects can produce diminishing efficiency of electrophilic astatination reactions due to increasing deposition of radiation dose with increasing activities and with the passage of the time. Astatine-211 has chemical properties that permit complex labelling strategies and a longer half-life than 2¹³Bi that makes it more suitable when the targeting molecule does not gain immediate access to the tumour cells. The first clinical evaluation was published in 2001 [2] in patients with brain tumour. Although this study circumvents many of the challenges to entering clinical studies with ²¹¹At and many obstacles had to be surmounted before clinical studies could be initiated, several problems were encountered in maintaining efficient labelling with escalating radiation dose of α-particle even with fresh ²¹¹At elution [3]. Astatine-211 also has an additional hurdle to overcome before to its clinical application in labelled radiopharmaceuticals related with its production and distribution. Among the potential group of promising α- emitter it is the only one produced by cyclotrons, but due to the scarcity of cyclotrons equipped with 25−30 MeV α-particle beams, it will of necessity be utilized in distant locations from the site of production. It presents a major chemical challenge because the diminishing efficiency of electrophilic astatination reactions with the passage of the time is well known, a problem likely related to the radiolysis produced by the high LET (linear energy transfer) meaning that large amounts of energy are deposited in a highly localized manner. This problem has been most comprehensively investigated to understand and evaluate the role of the radiolysis effects of astatine alpha particles in the synthesis of therapeutic amounts of astatine labelled radiopharmaceuticals. The results of the study were published in three different papers

[en] In the framework of the CRP, our country has worked on the optimization of synthesis, quality control, in vitro and in vivo evaluation of ¹²³I radiopharmaceuticals based on peptides. We have worked on selective labelling procedures using prosthetic groups with the goal to create a strong carbon-halogen bond, which will be resistant to in vivo dehalogenation and other catabolic processes. The method utilizes the labelling agent, reactive with ε-amino lysine groups, N-succinimidyl 3-iodobenzoate. This conjugation agent was radiolabelled by using an organometallic intermediate to facilitate the reaction. The organometallic N-succinimidyl 3-(tri-nbutylstannyl) benzoate (ATE) was made in a three-step synthesis pathway. The yields for the reactions of this synthetic pathway were: 56.4% for the first reaction, 67% for the second, and 58% for the ATE (469 mg, 0.92 mmol). Because of only 0.1 μmol of ATE is needed for the labelling of peptides, from one batch of organic synthesis we obtained ATE to make more than 9000 labelling. The N-succinimidyl 3-(tri-n-butylstannyl) benzoate (ATE) was radiolabelled in 55-85% radiochemical yield to obtain the N-succinimidyl 3-iodobenzoate ( [¹³¹I]SIB ). Parameters like reactive concentration and isolation method of the labelling agent were studied. The labelling agent [¹³¹I]SIB was subsequently conjugated to a human IgG and a peptide. A chemotactic peptide was used as a model peptide. A potent chemotactic peptide N-formyl-norleucyl-leucyl-phenylalanyl-norleucyltyrosyl- lysine (fNleLFNleYK) was derivatized by reaction with the labelling agent in 59-75% of radiochemical yield. This derivatized peptide bound specifically to human polymorphonuclear leukocytes in vitro and exhibited biological activity in a superoxide production assay. Binding affinity IC₅₀: 36 nM, in the displacing of [³H]fMLF binding, and IC₅₀: 68 nM, in the displacing of the fNleLFNleYK-[¹³¹I]SIB conjugate, for the derivatized peptide were obtained. Because of both IC₅₀ were higher of than those for the underivatized peptide the affinity of the derivatized peptide is somewhat lower than that. With the HPLC condition used the peaks corresponding to ¹³¹I-labelled peptide, unlabelled peptide and [¹³¹I]SIB are well resolved; so carrier free radiolabelled peptide can be isolated. Under these circumstances, the specific activity of the radiolabelled peptide is limited only by the specific activity of the radioiodine. The thyroid uptake of the radioiodinated peptide was very low. This result indicate that this radiohalogenation method yield a labelled molecule very stable to in vivo dehalogenation. Rapid localization (within 1 h) of radiolabelled chemotactic peptide at sites of experimental infection was observed. (author)

[en] One of the most important considerations in the development of radiopharmaceuticals for the targeted radiotherapy of cancers is the selection of the type of radiation emitted during the decay of the radionuclide. Alpha particle emitters have emerged as a promising approach for certain clinical applications such as compartmentally spread disease and neoplasms present in the blood. An attractive feature of radionuclides decaying by the emission of α particles is that they offer the prospect of matching the cell specific reactivity of targeting vehicles, such as receptor avid peptides and monoclonal antibodies, with radiation with a range of only a few cell diameters. In addition, α particles have important radiobiological advantages when compared with conventional external beam radiotherapy and α particles including a more potent cytotoxic effectiveness, with sterilizing potential nearly independent of oxygen concentration, dose rate and cell cycle position. This review summarizes the current status of targeted radiotherapy with α particle emitting radionuclides. Because they have reached the stage of clinical investigation, monoclonal antibodies labelled with the promising α particle emitting radionuclides ²¹³Bi, ²²⁵Ac and ²¹¹At will be highlighted. (author)

[en] Targeted α-particle radiotherapy is an appealing approach to cancer treatment because of the potential for delivering curative doses of radiation to tumor with minimal damage to normal tissue due to a range equivalent to only a few cell diameters. Compared with β-emitters they have significant advantages from a radiobiological perspective. The LET of ²¹¹At α-particles is more than 400 times higher than the β-particles emitted by ⁹⁰Y, in addition the distance between ionizing events is almost the same as that between the two strands of DNA, yielding a high probability of creating non-repairable DNA damage. It gives the ability to kill cancer cells not compromised by hypoxia, dose rate effects or cell cycle position, enhancing their attractiveness for targeted radiotherapy. However, translation of the concept to the clinic has been slow, many obstacles had to be surmounted before clinical studies could be initiated, the first clinical evaluation of a ²¹¹At- labeled mAb was made in 2001. This study circumvents many of the challenges to entering clinical studies with ²¹¹At. But several problems were encountered in maintaining efficient labeling with escalating radiation dose of alpha-particle likely related to radiolysis. The impact of the radiolysis produced by the α-particle over the labeling chemistry is much higher in comparison with typical β-emitters due to a deposition of energy in the solvent in a highly localized manner two orders of magnitude per unit volume higher than 90Y or ¹³¹I. Due to these difficulties a comprehensive basic science study about the radiolytic effects of astatine alpha-particles over the synthesis of ²¹¹At-labeled radiopharmaceuticals was carried out. Its main goal was overcoming the problem of the synthesis of ²¹¹At-labeled radiopharmaceuticals at the high activities necessaries for therapy and also to extend the shelf life of astatine elutions. Briefly this study held several steps, the first one was to study the role of solvent-related radiolytic effects over the astatination precursors in several solvents and pH. On the second step we studied the effect of the radiolysis-mediated process on the nature of the labeled product generated and the yields of the astatinated molecule used to label the mAb (SAB) as a function of the radiation dose and pH. Afterward we explored the effect of radiation dose on the astatine species present before initiation of the labeling reaction based on the hypothesis that ²¹¹At will react with highly reactive radiolytically generated species coming from the solvent, these studies were carried out only in methanol which the results from the previous two steps identified as the optimal solvent for astatodestannylation. The results of the studies showed that astatine chemistry critically depends on the solvent where the reaction is carried out. The α-particle-induced radiolytic effects mostly work through interaction with the solvent, consequently the mechanisms and kind of damage accountable for the decreasing on the astatination reactions yield will strongly depend on the solvent. Of the three solvent used as model of the solvent groups mostly utilized on the past to do astatination, aromatics, halogenated and alcohols, we showed that methanol was the optimal solvent for astatodestannylation. In benzene the solvent itself is pretty stable but the astatine is mostly trapped in reaction with the aromatic molecules. In chloroform there is a fast decreasing of astatination precursor mainly due to competitive reactions with free radicals coming from radiolytic degradation of the solvent (chlorine radicals mainly). In methanol the tin precursor remains largely intact with increasing radiation dose, instead the radioisotope itself is the most affected. The result probed that the astatine chemical form does become altered and converted to a reduced species with increasing radiation dose deposition to the solvent, the reation is also pH dependent; solid experimental evidence lead us to hypothesize that the reduced astatine is most likely astatide. This reduction reaction turns out to be a main deleterious effects over astatination reactions at the high activities required for therapeutic purpose. This study provided critical information to understand the chemistry of astatine and its microenvironment at high activities hence high radiation field. This information was used for studies focus on the stabilization of the astatine from the consequence of its own radiation field to make possible astatination reactions at the high activities that therapy requires. (author)

No abstract available

[en] The synthesis of the N-(4-iodo-2, 6-diethylphenylcarbamoylmethyl) iminodiacetic acid labelled with ¹⁴C at the carbonyl carbon atom which was required for metabolism studies is described. The complex formation between the title product and Tc-99m is also presented. (author)

No abstract available