Copyright All images in this presentation are the property of Jane Hanrahan unless otherwise referenced.

Dr Jane Hanrahan janeh@pharm.usyd.edu.au Radiopharmaceutics Dr Jane Hanrahan janeh@pharm.usyd.edu.au

Ideal Radiopharmaceuticals Maximum Diagnostic Information with Minimum Risk Half-life should be short - isotope has high specific activity ie rapid decay rate, high No. of dps per weight of material No particulate radiation emission - want pure g ie no -, + g energy high enough to be detected emanating from deep tissue - but low enough to be detected efficiently Ideal energies 120 to 240 keV

Ideal Radiopharmaceuticals Radionuclide should be an element with variable chemistry Enables preparation of a wide range of compounds for different diagnostic purposes Radioisotope should be carrier-free Want to maximise activity/g - no cold material, reduces toxicity problems Large scale production is achievable and economical

Technetium-99m (99mTc) T1/2 = 6.02 h Decays by isomeric transition High specific activity Decays by isomeric transition 99Mo 99mTc (excited state) 99Tc (ground state) Pure -emission with energy 140 keV Known valences 2, 3, 4, 5, 6, 7 Variable chemistry, most common Tc3+, Tc4+ Readily prepared carrier free

Technetium-99m (99mTc) 99Mo (67 h) 99mTc (6 h) 99Tc (2.1 x 105 y) 99Ru 86.3 % metastable 99Mo (67 h) 99mTc (6 h) 13.7 % Isomeric transition Pure  emission 99Tc (2.1 x 105 y) 99Ru (stable)

Radionuclide Generators Ideal Radionuclide Generator Sterile and pyrogen free Saline eluent Mild chemical conditions Room temperature storage Ideal gamma-emitting daughter nuclide No parent present in eluent Parent half-life short enough so that production of daughter is rapid enough, but not too rapid.

Radionuclide Generators Ideal Radionuclide Generator Daughter nuclide has varied chemistry to allow production of many different radiopharmaceuticals Grand-daughter nuclide is very long-lived or stable Shielding of generator is not too difficult Separation is simple and does not require a great deal of human intervention Generator is easily recharged by a readily available parent radionuclide

Radionuclide Generators http://nuclear.pharmacy.purdue.edu/what.php http://www.orau.org/ptp/collection/nuclearmedicine/tc99mgenerator.htm http://www.frankswebspace.org.uk/ScienceAndMaths/physics/physicsGCE/D1-1.htm

99Mo/99mTc Generator most widely used generator system mother nuclide 99Mo (t1/2=67 h) decays into the daughter nuclide 99mTc (t1/2=6 h) Milking cow analogy Basics of Radiopharmacy, B.A Rhodes & B.Y.Croft, Chapter 9, Generator Systems. (1978) http://www.clipartheaven.com/show/clipart/agriculture/milking_cow_6-gif.html

Other Generator Systems

Quality Control Impurities eluted with the Na99mTcO4 in the saline. Alumina Breakthrough Radiochemical purity pH Sterility Apyrogenicity

Quantification Radioactivity Activity Number of disintergrations per second (Bq) Rate of disappearance of radionuclide - dN dt  N - dN dt = kN where t 1/2 = ln2 k 1/2 t = ln2 k k=1 N = number of radioactive nuclei k= constant specific for each isotope

Quantification Exponential decay At = A0e-kt Radioactivity (Bq) time

Example 1 How many moles of 99Mo does 15 GBq represent, t1/2=67h N = - dN dt = kN 15 GBq = 15 x 10 9 Bq 1/2 t = ln2 k 15 x 10 9 dps = 0.693/(67x60x60) N = sec-1 2.89 x 10-6 = 2.89 x 10-6 sec-1 = 5.33 x 1015 atoms Avogadro’s No. = 6.023 x 1023 No. of moles = No. of atoms Avogadro’s No. = 5.33 x 1015 = 8.85 x 10-9 moles 6.023 x 1023

Example 2 How many grams of 99Mo does 15 GBq represent, t1/2=67h From previous slide 15 GBq = 8.85 x 10-9 moles 1 mole 99Mo = 99 gram Therefore 8.85 x 10-9 moles = 8.85 x 10-9 moles x 99 grams = 8.76 x 10-7 grams = 0.876 µg

Example 3 At = A0e-kt = 15e-(ln2/67)72 = 15 x 0.475 = 7.125 GBq 86.3 % of 99Mo decays to 99mTc with a half life of 67 hours. A 99mTc generator is filled with 15 GBq of 99Mo at 9 am on Friday morning and the 99mTc is eluted from the generator with 90 % efficiency, how much activity of 99mTc per ml can we get from the generator at 9 am on the following Monday morning in a 10ml elution. At = A0e-kt = 15e-(ln2/67)72 = 15 x 0.475 = 7.125 GBq 99mTc activity in generator = 0.863 x 7.125 = 6.149 GBq Amount eluted = 0.9 x 6.149 = 5.53 GBq = 0.553 GBq/ml = 553 MBq/ml

Example 4 At 9am, solution has 533 MBq/ml At 2 pm on the same Monday as the original elution, what volume of the previously eluted solution would need to be dispensed for a skeletal scan requiring 250 MBq of 99mTc. t1/2 99mTc = 6 h At 9am, solution has 533 MBq/ml Therefore at 1 pm, activity of solution is At = A0e-kt = 553e-(ln2/6)5 = 533 x 0.578 = 307.9 MBq/ml For 250 MBq, volume of solution = 250/308 = 0.81 ml

Mechanism of Localisation Simple Diffusion - net movement of particles (molecules) is from an area of high concentration to low concentration. - normal versus abnormal distribution using Na99mTcO4 eg breakdown of blood brain barrier due to tumours or infarct damage in brain

Mechanism of Localisation Active transport Uptake radionuclide from blood using normal biochemical processes e.g. thyroid trapping of 123I or Na99mTcO4 or hepato-billiary imaging Renal imaging - 99mTc complexed with DTPA (diethylene triamine pentaacetic acid) Outflow obstruction Renal artery narrowing Vesico-uretic reflux Renal transplant assessment 2 TcO4- + 3 Sn2+ + 16 H+ Tc4+ + 3 Sn4+ + 3 H2O DTPA

Renal Imaging with 99mTc-DTPA

Mechanism of Localisation Cell Sequestration Liver, spleen and bone marrow uptake of colloidal particles by reticulo-endothelial (Kupfer) cells eg technetium sulfide colloid 99mTc2S4 Renal imaging Particle size ~ 0.1 µm trapped in liver or spleen Re2S7 is used as a carrier 2HCl + 2 Na2S2O4 H2SO4 + 2 NaCl + H2S + SO2 2 H+ + 7 H2S + 2 TcO4- Tc2S7 + 8 H2O

Mechanism of Localisation Capilliary Blockade Large particles trapped by lung arterioles (~ 20 µm) eg for pulmonary perfusion studies 99mTc labeled macroaggregated albumin (MAA) or 99mTc labeled macroaggregated ferric hydroxide Ventilation studies - radioactive gas 133Xe or aerosol radiopharmaceuticals 99mTc as carbide - “Technegas” 99mTc as sulfur colloid Inhallation then washout - airway obstruction “hotspot” TcO4- Tc4+ Tc(OH)4 reduction -OH + FeSO4

Capilliary Blockade

Mechanism of Localisation Compartmental localisation - placement of a radiopharmaceutical in a fluid space and maintaining it there long enough to image that fluid space. e.g. Retention of labeled 99mTc-labelled RBC or proteins in vascular pools Methods Remove blood sample & incubate with Na99mTcO4 for 15 min and then administer “Pre-tinning” - administer SnCl2 in saline, wait 30 min, then administer labelled RBC ( ~ 700 MBq Na99mTcO4) “Gated” heart studies - collect images in synchrony with ECG at rest and under stress

Labeling RBCs

Mechanism of Localisation Chemisorption interaction of labelled phosphate complexes with bone Skeletal imaging - metabolically active sites - soft tissue tumours - metastatic lesions - rheumatoid arthritis Methylene diphosphate Na99mTcO4 + SnCl2 Tc4+ + phosphate compound

Mechanism of Localisation Specific cell binding preferential uptake by tumour cells eg labelled tumour associated marker compounds or monoclonal antibodies

Radiopharmaceuticals for Tumour Imaging 131I (sodium iodide) - thyroid 67Ga (gallium citrate) - lymphoma, hodgkin’s disease, lung tumours, bone tumors - Decays by electron capture (EC) t1/2 78 h - g energies, 93 keV (40 %), 184 keV (24 %), 296 keV (22 %) - 67Ga binds to transferin in plasma - Biodistribution is non-specific - Uptake is influenced by a number of factors

Radiopharmaceuticals for Tumour Imaging 111In (complexed with Bleomycin or monoclonal antibodies) - t1/2 78 h -  energies, 173 keV and 247 keV protein chelating groups

Mechanism of Localisation 8. Specific Receptor Binding Mainly in CNS [11C]-Raclopride (dopamine receptor antagonist [11C]-Flumazenil at GABA-benzodiazepine site