Nuclear Medicine Physics Radioactivity and Radioactive Decay Radionuclide Production Jerry Allison, Ph.D. Department of Radiology and Imaging Medical College of Georgia

Medical College of Georgia And Sameer Tipnis, Ph.D. A note of thanks to Z. J. Cao, Ph.D. Medical College of Georgia And Sameer Tipnis, Ph.D. G. Donald Frey, Ph.D. Medical University of South Carolina for Sharing nuclear medicine presentation content

A Review Nuclear decay rules Based on conservation laws -decay: AXZ  AYZ+1 + e- + ~ -decay: AXZ  AYZ-1 + e+ +  e-capture: AXZ + e-  AYZ-1 +  -decay and internal conversion: no changes for A & Z

Nuclear decay scheme +-decay and EC (electron capture) F18 (FDG): cancer, myocardial disease, etc. Sometimes drawn with vertical drop of 1.02 MeV for positron emission (rest mass equivalence of 2 electron electron masses) Also Rb 82 for myocardial imaging

Nuclear decay scheme EC (electron capture) Ga67 (gallium citrate): tumor localization Ga-67 used in tumor localization Also In-111, I-123, I-125 and Tl-201 No beta to contribute to dose

Nuclear decay scheme --decay I131 (NaI): thyroid disorders and cancer

Nuclear decay scheme -decay Tc99m (various compounds): various uses

Following - and + decay and Electron Capture g-ray emission or internal conversion follows if the child nucleus is in an excited state Any resultant electron vacancies are resolved through emission of characteristic X-rays and/or Auger electrons (radiation dose with no imaging benefit)

Question Match the decay mode to the description below: A. beta minus decay B. beta plus decay C. alpha decay D. isomeric transition   1. Ra-226 to Rn-222 2. Z increases by 1 3. Z decreases by 1 4. Z decreases by 2 5. A and Z remain constant 6. tritium (H-3) to helium (He-3) 7. Tc-99m to Tc-99 8. Electron capture can be a competing mode of decay A to 2 A to 6 B to 3 B to 8 C to 1 C to 4 D to 5 D to 7

Radioactivity : decay constant with units of 1/sec or 1/hr A (t): disintegration rate at time t (decays/sec) N(t): number of nuclei at time t : decay constant with units of 1/sec or 1/hr  = ln2/T1/2 = 0.693/T1/2 half life: T1/2 = ln2/ = 0.693/

Radioactivity unit in SI: 1 Bq = 1 disintegrations per second (Becquerel) traditional unit: 1 Ci = 3.7×1010 dps (1g of Ra-226, extracted first by Mme. Curie) 1 mCi = 37 MBq NM imaging: ~ 1 to 30 mCi (30 – 1100 MBq)

Question How many F-18 atoms are there in 10 mCi of FDG? (T1/2 = 110 min) A. 3.5 × 1019 B. 3.5 × 1016 C. 3.5 × 1012 D. 3.5 × 109 E. 3.5 × 106 A = lN N = A/l A = 10×3.7×107/s = 0.693/(110×60s) N = A/l = 3.5×1012

Radioactivity decay equation: A(t) = A0 exp(-t)

Physical Half-life (Tp) Tp = time required for the number of radioactive atoms to reduce by one half Basic equations: Nt = N0e-t or At = A0e-t Tp = 0.693 /   = 0.693 / Tp N0 = Initial number of radioactive atoms Nt = number of radioactive atoms at time t 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Physical Half-life (Tp) Tp = time required for the number of radioactive atoms to reduce by one half Basic equations: Nt = N0e-t or At = A0e-t Tp = 0.693 /   = 0.693 / Tp N0 = Initial number of radioactive atoms Nt = number of radioactive atoms at time t 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

8 t1/2  ~ 0.4% 10 t1/2  ~ 0.1% 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

A0 = 500 Ci ; t = 2 days = 48 hr; Tp = 67 hr A pt is injected with 500 Ci of 111In (Tp = 67 hrs). The patient is imaged 2 days later. Assuming none of the activity is excreted, what is the remaining activity at the time of imaging? A0 = 500 Ci ; t = 2 days = 48 hr; Tp = 67 hr At = A0e-t  = 0.693/Tp = 0.693/67 hr = 0.0103 hr-1 t = 0.0103 hr-1 x 48 hr = 0.494  0.5 At = 500 Ci x e-0.5 = 303 Ci 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Indium In-111 decays by electron capture to cadmium Cd-111 (stable) Physical half-life of 67.32 hours (2.81 days). Photons useful for detection and imaging are: Gamma 2, 90% abundant, 171 keV Gamma 3, 94% abundant, 245 keV Marketed as ProstaScint by Mallinckrodt for imaging of prostate cancer cells Also used to label white blood cells for detection of inflammation

Biologic Half-life (Tb) Tb = Time taken to reduce the amount of radiopharmaceutical in the body by one half due to various clearance mechanisms (excreta, perspiration, etc.) 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Effective half life Te = Time to reduce radiopharmaceutical in the body by one half due to functional clearance and radioactive decay 𝟏 𝐓𝐞 = 𝟏 𝐓𝐩 + 𝟏 𝐓𝒃 Te = 𝐓𝐩𝐓𝐛 𝐓𝐩+𝐓𝐛 if Tp >> Tb, Te ≈ Tb if Tp << Tb, Te ≈ Tp

A pt is injected with 100 mCi (Tp = 8 days; Tb = 4 days ) A pt is injected with 100 mCi (Tp = 8 days; Tb = 4 days ). What is activity in the pt after 8 days? Te = TpTb/Tp+Tb = 2.67d = 0.693 / Te = 0.693 / 2.67 d = 0.26 d-1  t = 0.26 d-1 x 8 d = 2.1  2.0 A0 = 100 mCi At = A0e-t At = 100 mCi x e-2 = 13.5 mCi 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Radioisotope production Fission (Reactor produced) 99Mo, 131I, 133Xe Cyclotron produced Neutron activation (Reactor produced) Generator: transient equilibrium 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Cyclotron-produced radionuclides for PET: 11B(p,n)11C 15N(p,n)15O 16O(p,a)13N 18O(p,n)18F for gamma camera: 111Cd(p,n)111In p 11B 11C n

Biosynthesizer (hot cell) Used to attach the cyclotron-produced radionuclide to a biological compound, e.g. F-18 to FDG (2-deoxy-2-[18F]fluoro-D-glucose)

Biosynthesizer (hot cell)

Neutron activation Samples bombarded with the large neutron flux in a reactor 14N(n,p)14C 23Na(n,g)24Na 31P(n,g)32P 124Xe(n,g)125Xe  125I 130Te(n,g)131Te  131I

Parent-daughter decay schemes Transient equilibrium: Tp > Td 99Mo42  99mTc43 + e- + 66 h 87.6% 99mTc43 99Tc43 + 6 h They decay in parallel after tmax to achieve equilibrium. tmax= 24 hr for Mo-Tc equilibrium 𝑨𝒅(𝒕) 𝑨𝒑(𝒕) = 𝑻𝒑 𝑻𝒑−𝑻𝒅 (1.1 for 99mTc/99Mo) 𝑨𝒅(𝒕)/𝑨𝒑 𝒕 = 1.1 for 99mTc/99Mo which times the branching ratio of 0.876 for MO-99 -> 0.964 so Tc-99m is 3.6% below Mo-99 at equilibrium

Transient equilibrium 1.1 x .876 For 99mTc, Max yield ~ 24 hrs ~3 Curies of Mo99 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Generator-produced radionuclides produce radionuclides using different chemical properties between the parent and child parent T1/2 child decay T1/2 82Sr 25d 82Rb b+,EC 1.3m 99Mo 66h 99mTc IT 6h

Nuclear decay scheme 99Mo42  99mTc43 + e- +  (87.6%) 99mTc43  99Tc43 +  1 4 2 . 7 k e V 5 9 T c 3 g % 8 I C (6.01 h) m (2.111x105 y) g1

Transient equilibrium is the basis of: Mo-99 -> Tc99m generator and Sr-82 -> Rb-82 generator 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Tc-99m generator components: alumina column, lead shield, air filter, saline eluent MoO4-- bound to alumina (Al2O3) but 99mTcO4- not strongly bound eluted with 5 to 25 ml saline: ~80 - 90% 99mTc washed out in one elution Molybdate; Dioxido(dioxo)molybdenum

99mTc generator Molybdate; Dioxido(dioxo)molybdenum 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Tc-99m generator maximum activity available at 24 hr usable activity available every 3 to 6 hr Commercial generators are sterilized, shielded, and largely automated. © Physics in Nuclear Medicine: Cherry, Sorenson and Phelps, 4th edition, 2012

Tc-99m generator Mo-99 decays to Tc- 99m 87.6% of the time (decays directly to ground state of Tc- 99 12.4% of the time) © Physics in Nuclear Medicine: Cherry, Sorenson and Phelps, 4th edition, 2012

99mTc yield 99Mo generator typically delivered weekly A ~ 1 to 2 Ci Maximum 99mTc yield ~ 24 hours About ½ of Max. yield @ 6 hrs after elution As the week progresses Mo decays and Tc yield goes down Eg. Monday:1.5 Ci of 99Mo (new generator) Monday yield: 1.2 Ci of 99mTc in 10 mL eluate Friday yield : ~ 0.5 Ci of 99mTc in 10 mL eluate 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Major impurities from the generator The eluate from a generator contains Tc- 99m and possibly tiny quantity of Mo-99. Also a small quantity of Al+++ may come out with eluate.

99mTc QC Goal – to have the least amount of contaminants (Mo, alumina) in the eluate 99Mo has high energy s (740 – 780 keV), and contributes to pt dose by  Al+++ interferes with labeling process, clumps RBCs and can cause microemboli “Moly breakthrough” test – at first elution 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Impurity limits Test Frequency Limit Mo-99 Every elution < 0.15 mCi Mo breakthrough: (initial elution per mCi Tc radiation dose by NRC) at tadm Al+++ Every elution <10 ppm breakthrough: (initial elution at tadm clumping of by NRC) may RBC and be expressed micro-emboli as mg/ml)

Mo-99 breakthrough limit at elution Due to the slower decay of Mo-99, the limit at time of elution must be smaller than 0.15 mCi Mo-99 per mCi Tc-99m in order to ensure the limit at time of administration. E.g. the ratio is 0.042 mCi Mo-99 per mCi Tc-99m at time of elution increases to 0.15 12 hr later. 1 mCi Tc-99m  0.25 mCi 12 hr later 0.042 mCi Mo-99  0.037 mCi 12 hr later 0.037/0.25 = 0.148 < 0.15

Ratio of (1) to (2) gives amount of Mo 99mTc QC Place vial of eluate in Pb container, measure activity. This represents ONLY the Mo activity Place vial in plastic sleeve, measure activity. This represents BOTH Mo and Tc Ratio of (1) to (2) gives amount of Mo 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Aluminum ion (Al+++) breakthrough Al3+ ion is measured colorimetrically. A drop of the eluate is placed on one end of a test paper and a drop of a standard solution of Al3+ with a concentration of 10 ppm is placed on the other end of the test strip. If the color at the center of the drop of eluate is less red than that of the standard solution, the eluate passes the ion breakthrough test. 10 ppm Al3+ standard generator eluate

99mTc – a workhorse in NM! T1/2 = 6 hr – ideally suited to study metabolic processes in patients 140 keV emission - low patient dose & ideal for gamma cameras No high-energy - radiation – low pt dose Versatile chemistry - can form tracers by being incorporated into a range of biologically-active substances to target tissue or organ of interest 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Ideal imaging radiopharmaceuticals Gamma energy 60 - 511 keV photons high enough to escape patient (lowers pt dose) but low enough to be detected (high detection efficiency) Half life several minutes to days to allow enough uptake in tissue and fast clearance from blood High target / background ratio Limited contamination, e.g. Tc-99m/Mo-99 > 99.985% Chemical properties: easy to attach to a wide range of biochemical compounds Cost-effective and convenient 2015 Nuclear Medicine Physics for Radiology Residents Sameer Tipnis, PhD, DABR

Radionuclides used in nuclear medicine Less than 20 radionuclides but hundreds of labeled compounds © Physics in Nuclear Medicine: Cherry, Sorenson and Phelps, 4th edition, 2012

Selected clinical nuclear medicine procedures © Physics in Nuclear Medicine: Cherry, Sorenson and Phelps, 4th edition, 2012

Radiopharmaceutical preparation Radiopharmaceutical is a compound attached with a radionuclide: Tc-99m MDP (bone metastasis) Tc-99m sestamibi (myocardial perfusion) Or using ionic form e.g. NaI (I--131), TCl (Tl+-201) It determines the biodistribution  How much radioactivity goes to an organ? It determines the biological half life  How much radioactivity remains in an organ? Safety requirements: non-toxic, sterile, and pyrogen-free

Tc-99m labeled radiopharmaceuticals Mix of 99mTcO4_ (pertechnetate) and a cold kit containing a reducing agent (stannous chloride) to lower oxidation states and to bind to a ligand © Physics in Nuclear Medicine: Cherry, Sorenson and Phelps, 4th edition, 2012