Radionuclide therapy using bone targeting radiopharmaceuticals is an effective palliative care option to reduce pain associated with advanced disease with bone metastases. Over the last 20 years, suitable therapeutic radionuclides are more widely available, meaning that the benefits of pain palliation therapy could reach more patients. This publication provides a broad overview on the current status of radiopharmaceuticals for bone pain palliation. It covers production of radionuclides, identification of bone seeking carrier molecules, preparation of stable complexes, in vitro and in vivo evaluations and dosimetry studies which are part of the development of these radiopharmaceuticals for clinical use. Details on production and quality control of the currently available products, provided here will be of use to scientists involved in the development of these radiopharmaceuticals.

• 1. INTRODUCTION
  • 1.1. Background
  • 1.2. Objective
  • 1.3. Scope
  • 1.4. Structure
• 2. BONE METASTASIS AND MANAGEMENT
  • 2.1. Bone
  • 2.2. Bone metastasis
  • 2.3. Effect of bone metastasis
  • 2.4. Diagnosis of bone metastasis
  • 2.5. Management of bone metastasis with therapeutic drugs
    • 2.5.1. Non-steroidal anti-inflammatory drugs
    • 2.5.2. Opioids
    • 2.5.3. Corticosteroids
    • 2.5.4. Growth factors, signalling molecules and receptor antagonists
    • 2.5.5. Bisphosphonates
    • 2.5.6. Denosumab
  • 2.6. Management of bone metastasis with radiation
    • 2.6.1. General principles for the use of ionizing radiation for cancer management
    • 2.6.2. External beam radiation therapy
    • 2.6.3. Targeted radionuclide therapy
• 3. DESIGN OF BONE PAIN PALLIATION AGENTS
  • 3.1. Bone seeking radiopharmaceuticals
  • 3.2. In vivo uptake mechanisms of bone seeking radiopharmaceuticals
    • 3.2.1. Radionuclides that mimic calcium as bone seeking radiopharmaceuticals
    • 3.2.2. Radiopharmaceuticals that are taken up by hydroxy apatite particles
    • 3.2.3. Radiopharmaceuticals that are radiolabelled with bifunctional chelating agents (BFCA) conjugated to target seeking molecules
  • 3.3. Development of bone seeking radiopharmaceuticals
    • 3.3.1. Selection of radionuclides
    • 3.3.2. Selection criteria for carrier molecules
    • 3.3.3. Radiolabelling
    • 3.3.4. Stability of radiometal complexes
    • 3.3.5. Radiolabelling conditions
  • 3.4. Pre-clinical studies
  • 3.5. Clinical trials
  • 3.6. Approval
  • 3.7. Good manufacturing practices for radiopharmaceutical production
• 4. RADIONUCLIDES FOR BONE PAIN PALLIATION
  • 4.1. General principles for the production of radionuclides
    • 4.1.1. Cyclotron production of radionuclides
    • 4.1.2. Reactor production of radionuclides
    • 4.1.3. Generator production of radionuclides
    • 4.1.4. Isolation from long lived actinides
  • 4.2. Production of β− particle emitting radionuclides
    • 4.2.1. 32P
    • 4.2.2. 89Sr
    • 4.2.3. 153Sm
    • 4.2.4. 177Lu
    • 4.2.5. 186Re
    • 4.2.6. 188Re
    • 4.2.7. 117mSn
    • 4.2.8. 170Tm
    • 4.2.9. 175Yb
    • 4.2.10. 166Ho
    • 4.2.11. 90Y
    • 4.2.12. 161Tb
    • 4.2.13. 169Er
  • 4.3. Production of alpha particle emitting radionuclides
    • 4.3.1. 225Ac
    • 4.3.2. 223Rn
• 5. PRE-CLINICAL EVALUATION OF BONE PAIN PALLIATION AGENTS
  • 5.1. Introduction
  • 5.2. In vitro cellular studies
    • 5.2.1. Binding efficiency of bone seeking radiopharmaceuticals towards bone matrix
    • 5.2.2. Studies to determine the cellular toxicity of bone seeking radiopharmaceuticals
    • 5.2.3. Study of apoptotic cell death
  • 5.3. In vivo pre-clinical studies
    • 5.3.1. Pharmacokinetic evaluation and biodistribution study
    • 5.3.2. Animal models for bone metastasis
  • 5.4. Conclusion
• 6. DOSIMETRY CALCULATION FOR ADMINISTERED RADIOPHARMACEUTICALS
  • 6.1. Dosimetry
  • 6.2. Dosimetry in targeted radionuclide therapy
  • 6.3. Dosimetric formalism and application to small scale dosimetry
  • 6.4. Dosimetry of penetrating vs non-penetrating radiation
  • 6.5. Cellular dosimetry
  • 6.6. Tissue and small scale dosimetry
  • 6.7. Application to small animal studies
  • 6.8. Conclusion
• 7. BONE PAIN PALLIATION RADIOPHARMACEUTICALS
  • 7.1. Current status of bone pain palliation agents
  • 7.2. Bone pain palliation agents with well established clinical use
    • 7.2.1. 32P
    • 7.2.2. 89SrCl2 (metastron)
    • 7.2.3. 153Sm–EDTMP (quadramet)
    • 7.2.4. 188Re HEDP
    • 7.2.5. 223RaCl2 (alpharadin) (xofigo)
  • 7.3. Bone pain palliation agents that are clinically tested
    • 7.3.1. 186Re HEDP (etidronate)
    • 7.3.2. 117mSn DTPA
    • 7.3.3. 177Lu–EDTMP
    • 7.3.4. 177Lu–DOTMP
    • 7.3.5. 153Sm–DOTMP
    • 7.3.6. 170Tm–EDTMP
  • 7.4. Bone pain palliation agents radiolabelled using bifunctional chelating agents (BFCAs)
    • 7.4.1. 177Lu–BPAMD
    • 7.4.2. 177Lu–DOTAzol
    • 7.4.3. 225Ac–DOTAzol for targeted alpha therapy
  • 7.5. Conclusion
• 8. TARGET SPECIFIC RADIOPHARMACEUTICALS (TSRs)
  • 8.1. Targeted radionuclide therapy
  • 8.2. Desirable features of target seeking radiopharmaceuticals for therapy
  • 8.3. Target specific radiopharmaceuticals for prostate cancer
    • 8.3.1. PSMA enzyme and its action
    • 8.3.2. TSRs based on the enzyme activity of PSMA and prostate cancer imaging
    • 8.3.3. PSMA inhibitor ligands for therapy of prostate cancer
    • 8.3.4. Synthesis of PMSA ligands
  • 8.4. TSRs based on chemokine receptor-4 (CXCR-4) ligands
  • 8.5. TSRs based on FAP inhibitor ligands
  • 8.6. Conclusion
• 9. FORMULATION OF BONE SEEKING RADIOPHARMACEUTICALS
  • 9.1. HEDP (etidronate)
    • 9.1.1. Reagents
    • 9.1.2. Chemical composition of kit
    • 9.1.3. Manufacturing formula for 22 vials
    • 9.1.4. Preparation of kit solution for a batch of 20 vials of HEDP kits
    • 9.1.5. Storage of HEDP kits and Solution C and D
    • 9.1.6. Radiolabelling
    • 9.1.7. Quality control
    • 9.1.8. Shelf life of 188Re–HEDP prepared using freeze-dried HEDP kits
  • 9.2. EDTMP
    • 9.2.1. Reagents
    • 9.2.2. Chemical composition of kit
    • 9.2.3. Manufacturing formula for 100 EDTMP kit vials
    • 9.2.4. Preparation of kit solution for a batch of 22 vials of EDTMP kits
    • 9.2.5. Storage of EDTMP kits
    • 9.2.6. Formulation of patient dose of 153Sm/170Tm/177Lu–EDTMP
    • 9.2.7. Quality control
    • 9.2.8. Shelf life of 153Sm/170Tm/177Lu–EDTMP prepared using freeze-dried kits
  • 9.3. DOTMP
    • 9.3.1. Reagents
    • 9.3.2. Chemical composition of kit
    • 9.3.3. Manufacturing formula for 100 DOTMP kit vials
    • 9.3.4. Preparation of kit solution for a batch of 100 vials of DOTMP kits
    • 9.3.5. Storage of DOTMP kits
    • 9.3.6. Formulation of patient dose of 153Sm/177Lu–DOTMP
    • 9.3.7. Quality control
    • 9.3.8. Shelf life of 153Sm/177Lu–DOTMP prepared using freeze-dried kits
  • 9.4. Preparation of 177Lu–PSMA-617 injectable solution
    • 9.4.1. Reagents and materials
    • 9.4.2. Preparation of reagents
    • 9.4.3. Preparation of 177Lu–PSMA
    • 9.4.4. Purification
    • 9.4.5. Quality control
    • 9.4.6. Preparation of 177Lu–PSMA-617 with CA-177Lu
  • 9.5. Preparation of 225Ac–PSMA-617
• REFERENCES
• ABBREVIATIONS
• CONTRIBUTORS TO DRAFTING AND REVIEW