Yttrium-90 and Rhenium-188 Radiopharmaceuticals for Radionuclide Therapy

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188 W/ 188 Re transportable generator system analogous to the 99 Mo/ 99m Tc generator, availability of a freeze-dried kit formulation adequate for hospital use would be highly convenient, particularly for the routine application of the IART approach. However, no example of this type has been reported so far for the preparation of 188 Re biotin derivatives. In the following sections, all steps involved in the development of a useful 188 Re biotinylated derivative will be described, including the molecular design, the chemistry employed for the high yield preparation and the development of a freeze-dried kit formulation. 8.2. DESIGN OF 188 Re BIOTIN COMPLEXES A fundamental prerequisite for developing a therapeutic agent with some potential clinical utility is to afford a final metallic conjugate showing high chemical inertness and stability under physiological conditions. The design of a robust 188 Re conjugate can be achieved through a careful selection of the most stable rhenium cores. A rhenium atom tightly bound to some characteristic ligand forms these functional groups that usually are strongly resistant to hydrolysis by water molecules. The rhenium(V) nitride, [Re≡N] 2+ and the rhenium(I) triscarbonyl, [Re(CO)] 3+ cores are among the most stable chemical fragments. In this study, the [ 188 Re≡N] 2+ core has been selected as a basic functional motif for the preparation of biotinylated 188 Re derivatives [8.13, 8.14]. Obviously, the intrinsic stability of this core has to be complemented by the concomitant coordination of a suitable set of ancillary ligands completing the coordination sphere. The essential features of the selected molecular arrangement for these complexes are schematically illustrated in Fig. 8.1(a). This class of compounds is composed of an apical 188 Re≡N group surrounded by a tridentate dianionic ligand (XYW) and a monodentate tertiary phosphine ligand (PR 3 ) spanning the four coordination positions on the basal plane of a distorted square pyramidal geometry (thus, the acronym of 3 + 1 complexes). Ligands possessing the 2,2’-diemrcapto diethylamine (SNS) {[S(CH 2 ) 3 NH(CH 2 ) 3 S] –2 } set of coordinating atoms provide a convenient source of XYZ type ligands. In Fig. 8.1(b), the crystal structure of a Re(V) nitride complex incorporating the simple SNS ligand and triphenylphosphine is reported. The SNS type tridentate chelating system utilized here was obtained by tethering two cysteine residues (cys–cys), as shown in Fig. 8.2(a), whereas the monodentate phosphines were (triscyanoethyl)phosphine (PCN) and 1,3,5-triaza-7-phosphaadamantane (PTA) (see Fig. 8.2(b)). 122
(a) FIG. 8.1. (a) Schematic illustration of the structure of 3 + 1 rhenium(V) nitride complexes and (b) crystal structure of the complex [Re(N)(SNS)(PPh3)] (PPh3 = triphenylphosphine; SNS = 2,2’-diemrcapto diethylamine). (b) (a) (b) FIG. 8.2. (a) The cys–cys chelating system for the Re(V) nitride core and (b) the monophosphines PCN and PTA utilized in this study. 123
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IAEA RADIOISOTOPES AND RADIOPHARMAC
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YTTRIUM-90 AND RHENIUM-188 RADIOPHA
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IAEA RADIOISOTOPES AND RADIOPHARMAC
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FOREWORD The IAEA helps to promote
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CONTENTS CHAPTER 1. INTRODUCTION ..
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7.4. Discussion ...................
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CHAPTER 12. DEVELOPMENT OF 90 Sr/ 9
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Chapter 1 INTRODUCTION 1.1. BACKGRO
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devices were designed to improve th
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etention of the antibody’s target
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Binding affinity of these derivativ
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Chapter 2 FUNDAMENTAL CONCEPTS IN R
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A special characteristic of radioph
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β particles emitted by 90 Y. Numer
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2.3.1. Exploitation of certain meta
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2.3.3. Antibodies The high specific
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cell cultures, presents one example
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Another very promising form of radi
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destructive processes within the jo
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esearch efforts, since then. Howeve
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[2.18] HAMILTON, J.G., The metaboli
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[2.52] GOLDENBERG, D.M., et al., Mu
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Chapter 3 DEVELOPMENT OF RADIOPHARM
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FIG. 3.3. Elution efficiencies for
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FIG. 3.5. Electrodeposition of yttr
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The results of the experiments of r
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TABLE 3.3. RESULTS FOR 90 Sr/ 90 Y
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FIG. 3.11. Elution yield of a 90 Sr
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According to Fig. 3.12, there is a
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eagent (Sigma). The mean recovery o
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FIG. 3.18. Variation of RCP (%) of
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(20 and 30 min) and volume of 188 R
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FIG. 3.24. Variation of labelling y
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(c) Clodronate: 20 mg of clodronate
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Chapter 4 EVALUATION OF THE 90 Sr/
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Kamadhenu consists of five main com
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Quality control of radiolabelling w
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The electrochemical deposition of 9
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FIG. 4.5. Typical pattern of the wh
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FIG. 4.6. Elution profile from the
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FIG. 4.8. CD20 recognition in Ramos
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4.5. RECOMMENDATIONS AND FUTURE WOR
Page 85 and 86: adioiodine labelled anti-NCAM antib
Page 87 and 88: FIG. 5.1. Comparison of biodistribu
Page 89 and 90: FIG. 5.3. Three step strategy. Biot
Page 91 and 92: TABLE 5.1. THREE STEP PRETARGETING:
Page 93 and 94: 5.1.4. Therapeutic experiments with
Page 95 and 96: 5.1.4.4. Conclusion The radioiodine
Page 97 and 98: control procedure for detection of
Page 99 and 100: 6.1.3. Recovery of doped 85/89 Sr 2
Page 101 and 102: 6.2. PREPARATION AND BIOEVALUATION
Page 103 and 104: (a) (b) (c) FIG. 6.5. PD-10 column
Page 105 and 106: FIG. 6.7. SDS PAGE pattern of ritux
Page 107 and 108: FIG. 6.10. HPLC pattern of pure 90
Page 109 and 110: FIG. 6.13. Cell binding studies wit
Page 111 and 112: 6.2.1.6. Conclusion The procedure f
Page 113 and 114: FIG. 6.17. Elution profile of 90 Y
Page 115 and 116: form NADH, which, in turn, causes t
Page 117 and 118: FIG. 6.19. In vivo distribution pat
Page 119 and 120: ACKNOWLEDGEMENTS The authors of thi
Page 121 and 122: Chapter 7 DEVELOPMENT OF THERAPEUTI
Page 123 and 124: the residual breast tissue becoming
Page 125 and 126: 7.2.5.2. Automatic procedure The la
Page 127 and 128: FIG. 7.2. RCP values of 90 Y r-BHD
Page 129 and 130: FIG. 7.3. Pyrogen test shows result
Page 131 and 132: to avidin at the 1:4 avidin:r-BHD m
Page 133 and 134: [7.9] SU, F.M., GUSTAVSON, L.M., AX
Page 135: 8.1. INTRODUCTION In past years, th
Page 139 and 140: Preliminary synthesis of the biotin
Page 141 and 142: (a) (b) FIG. 8.4. (a) PEGylated and
Page 143 and 144: TABLE 8.2. BIODISTRIBUTION IN RATS
Page 145 and 146: A specific binding to avidin was ev
Page 147 and 148: [8.13] BOSCHI, A., DUATTI, A., UCCE
Page 149 and 150: 90 Y solution obtained from a 90 Sr
Page 151 and 152: From each fraction, a ~1 g aliquot
Page 153 and 154: FIG. 9.2. Relationship between 90 S
Page 155 and 156: with 188 Re obtained from the 188 W
Page 157 and 158: 9.3.2. Labelling of DPA ale DPA ale
Page 159 and 160: FIG. 9.8. TLC radiochromatogram of
Page 161 and 162: (-) 188 Re(CO) 3 (+) (-) 99m Tc(CO)
Page 163 and 164: the HSA solution containing sodium
Page 165 and 166: TABLE 9.3. RESULTS OF 99m Tc LABELL
Page 167 and 168: 9.4.4. Yttrium-90 and 177 Lu labell
Page 169 and 170: FIG. 9.14. In vitro stability of 90
Page 171 and 172: (a) (b) (c) (d) (e) (f) (g) (h) (i)
Page 173 and 174: TABLE 9.8. YTTRIUM-90 CITRATE COLLO
Page 175 and 176: (a) (b) FIG. 9.17. Grain size distr
Page 177 and 178: TABLE 9.10. BIODISTRIBUTION AFTER A
Page 179 and 180: FIG. 9.19. Structure of DOTA biotin
Page 181 and 182: [9.8] WESTERA, G., GADZE, A., HORST
Page 183 and 184: Chapter 10 DEVELOPMENT, PREPARATION
Page 185 and 186: acidic pH) and the vial heated for
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10.2.2.1. Materials and methods (a)
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Using a semiquantitative method, th
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FIG. 10.3. Whole body, SPECT and ta
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TABLE 10.4. ORGAN DISTRIBUTION STUD
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was assessed by measuring the relea
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—— Biological studies: The whol
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or liver) (see Fig. 10.7). The resu
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(b) Results and discussion Healthy
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and the pellet (particles of HA lab
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FIG. 10.11. Organ distribution stud
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The procedure was as follows: —
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TABLE 10.5. INFLUENCE OF CHEMICAL I
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analysed using ICP OES was within t
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suggested for separation of pure 86
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adionuclidic purity of the 90 Y sol
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FIG. 10.16. (a) Strontium-90/yttriu
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[10.5] DJOKIĆ, D.J., JANKOVIĆ, D.
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Yttrium-90 is one of the radionucli
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(a) (b) (c) The generator was prepa
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—— Development of EPC: The EPC
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FIG. 11.4. Elution curve of 90 Sr e
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11.4. YTTRIUM-90 MAbs The use of th
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FIG. 11.6. RCP measured using ITLC
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FIG. 11.9. Biodistribution of 90 Y
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11.5. YTTRIUM-90 EDTMP Bone metasta
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FIG. 11.14. Electrophoresis of 90 Y
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FIG. 11.15. Particle size distribut
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11.7. CONCLUSION During this CRP, a
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Chapter 12 DEVELOPMENT OF 90 Sr/ 90
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12.1.1.4. Acid vapour trap and radi
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12.1.8. Yttrium-90 peptide labellin
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(a) FIG. 12.3. Yttrium-90 elution p
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FIG. 12.6. HPLC of 90 Y DOTATATE. 1
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Chapter 13 BIFUNCTIONAL BISPHOSPHON
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latter requirement [13.10]. When th
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whether the organometallic core sel
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The fate of a targeted imaging prob
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FIG. 13.7. SPECT/CT images showing
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FIG. 13.9. TLC SG analyses of [ 188
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FIG. 13.11. Stability study (toward
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Ex vivo biodistribution studies at
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was in the form of either pertechne
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FIG. 13.19. Absolute uptake of 99m
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[13.2] ZHANG, S., GANGAL, G., ULUDA
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[13.31] DE ROSALES, R.T.M., et al.,
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The activity due to 90 Sr should be
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14.3.1.2. Operation of the 90 Sr/ 9
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antibody were taken, to which 90 Y
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operation, radiopharmaceutical grad
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14.4.1.3. Operation of the stage II
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A typical EPC pattern for a 90 Y pr
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FIG. 14.10. Decay curve of carrier
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FIG. 14.12. ITLC of 90 Y rituximab.
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FIG. 14.13. Reaction scheme for lab
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TABLE 14.6. STABILITY (%) OF 90 Y D
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FIG. 14.18. Microsphere albumin siz
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[14.3] PANDEY, U., DHAMI, P.S., JAG
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naphthalene and 1.2 g of 2,5-diphen
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A-2.2. Materials The method for sep
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out using a Wallac 1411 spectromete
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A-5.3. Procedure The technique was
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Although acyclic chelators offer ma
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(b) (c) and 90 Y colloids, both ser
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CONTRIBUTORS TO DRAFTING AND REVIEW
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INDIA Allied Publishers 1 st Floor,
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A key requirement for the effective
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Yttrium-90 and Rhenium-188 Radiopharmaceuticals for Radionuclide Therapy

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