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Radiohalogens: Chemistry and Applications Michael Adam RADIOCHEMISTRY NUTS AND BOLTS II SNM 2008 Slides are not to be reproduced without permission of author. Applications Two main categories z Imaging z Therapy Slides are not to be reproduced without permission of author. Applications z With the exception of Brachytherapy and radioiodines, which localize in the thyroid and thyroid-originating cancers, for most practical purposes radiohalogens must be coupled with biomolecules (small and large) for imaging or therapy. Slides are not to be reproduced without permission of author. Radiohalogen Nuclides Slides are not to be reproduced without permission of author. Radiohalogen Production Most are produced on a cyclotron but some such as I125,131 are produced with a reactor. For more information see Pagani et al. Eur. J. Nucl. Med., 24, 1301, 1997. Slides are not to be reproduced without permission of author. Properties (t1/2 =110min, 97% β+, 0.635 MeV positron energy) 75Br (t =97 min), 1.74 MeV positron energy, 1/2 71%. 76Br (t =16.2hr), 3.98 MeV energy, 54%. 1/2 122I (t =3.6min) 1/2 123I (t =13.2 hr), commercially available 1/2 124I (t =4.18 d), emission not ideal but long t 1/2 1/2 125I (t =60d), Auger emitter and long t 1/2 1/2 77Br (t =57 hr), unavailable and high energy γ 1/2 z 18F z z z z z z z Slides are not to be reproduced without permission of author. Radiohalogens for Imaging z PET: 18F, 75Br, 76Br, 122I, 124I z SPECT: 77Br, 123I, Slides are not to be reproduced without permission of author. Choosing a Radiohalogen for Imaging z Physical properties z Half life z Availability z Labelling chemistry z In-vivo dose considerations Slides are not to be reproduced without permission of author. Radiohalogen Labeling Chemistry (eg. F-) z Electrophilic (eg. F2) z Nucleophilic Slides are not to be reproduced without permission of author. Nucleophilic Reactions anionic forms of halogens such as F-, Br-, or Iz Usually obtained directly from the cyclotron and can be used to exchange, displace or substitute other halogens or leaving groups. z For 18F- this is the most common labeling reaction. z Uses Slides are not to be reproduced without permission of author. Nuleophilic Examples Slides are not to be reproduced without permission of author. Nucleophilic Labelling Slides are not to be reproduced without permission of author. Nucleophilic Iodine Exchange Labeling Slides are not to be reproduced without permission of author. Nucleophilic Bromine Labeling Slides are not to be reproduced without permission of author. Electrophilic Halogen Labeling z Labeling occurs with an electro-positive form of the halogen (X+) z For F-18 requires an O-18 oxygen gas target and carrier F2 to produce 18F2. z For Br and I these can be obtained in an electropositive form by in-situ oxidation from the anion with agents such as Choramine-T, or Peracetic acid. Slides are not to be reproduced without permission of author. Electrophilic Examples Slides are not to be reproduced without permission of author. Electrophilic Labeling Slides are not to be reproduced without permission of author. Electrophilic Iodine Labeling Slides are not to be reproduced without permission of author. Electrophilic Bromine Labeling Slides are not to be reproduced without permission of author. Properties for Therapy z z z z z Must cause ionization and break bonds. Emit β-, β+, or Auger electron or α-particle Most commonly use is 131I for thyroid cancer (available, t1/2 8d, inexpensive but has high energy γ’s. 125I (Auger emitter), high LET but long half life. 211At, α emitter, high LET but less stable bond to carbon. Slides are not to be reproduced without permission of author. Radiohalogens for Therapy z 131I, 125I, 211At z Most studied is labelled monoclonal Antibodies (mAbs). z FDA approved 131I-mAb (Bexxar) for nonHodgkin’s Lymphoma. z Receptor binding peptides (somatostatin, bombesin, annexin etc.) z Small molecules such as 131I-MIBG Slides are not to be reproduced without permission of author. Radiohalogens for Therapy z 125IUDR, incorporates into DNA of rapidly growing cancer cells. z Radiohalogenated Steriods –therapy of hormone dependent tumors. z Radiohalogented Oligomers (DNA, RNA, PNA) bind to mRNA and DNA in cells. Slides are not to be reproduced without permission of author. In Vivo Stability has been a Problem with 211At-labeled biomolecules z Direct labeling of proteins with electrophilic 211At species results in an unstable attachment in vivo z A 2-step method for 211At labeling of biomolecules was developed using metallated aromatic and vinyl derivatives z Using 211At-labeled benzoates, slowly metabolized biomolecules (e.g. mAbs) are stable to in vivo deastatination but labeled biomolecules undergoing more rapid metabolism release free astatide Slides are not to be reproduced without permission of author. Radiohalogen Labeling of mAbs using Aryl Conjugates Comments: 1. Halobenzoates are stable to in vivo deiodination 2. Stannylbenzoates can be used to incorporate several halogens 3. Labeling process is more difficult and results in lower yields than direct radioiodinations Slides are not to be reproduced without permission of author. Anionic Boron-Cage Moieties Investigated for Radiohalogenations Slides are not to be reproduced without permission of author. Direct At-211 Labeling of mAbs using Borane Derivatives S H N HN O NH O O H N O O O H O O O H N NH O N H O NH O O O N H O N H O O O S O Protein O N N H Protein S O Slides are not to be reproduced without permission of author. Summary z Radiohalogenated Radiopharmaceuticals are an important area of Nuclear Medicine for imaging and therapy. z With the success of FDG there is now the infrastructure to develop other 18F agents z Future growth dependent on radiohalogen chemistry and labeling of biomolecules. Slides are not to be reproduced without permission of author. Questions 1. 2. 3. 4. 5. 6. List 4 radiohalogens Name one reactor produced radiohalogen Name the two most widely used radiohalogens in imaging Nucleophilic labeling uses what form of the radiohalogen Name two radiohalogens useful in therapy What kind of decay emission is useful for therapy. Slides are not to be reproduced without permission of author. Answers 1. 2. 3. 4. 5. 6. I-123, F-18, Br-75, At-211 (one from the table on slide 4) I-125, could be I-131 also I-123, F-18 Anionic (negatively charged) I-125, At-211 Beta, Alpha, Auger electron Slides are not to be reproduced without permission of author.