MICHAEL E. PHELPS, PH.D.ners580/ners-bioe_481/lectures/pdfs/Sorenson_chpt-5.pdfMICHAEL E. PHELPS,...

JAMES A. SORENSON, PH.D.

MICHAEL E. PHELPS, PH.D.Norton Simon ProfessorChair, Department of Molecular and Medical PharmacologyChief, Division of Nuclear MedicineUCLA School of MedicineLos Angeles, California

.

I SAUNDERS IAn Imprint of Elsevier Science

ProfessorDepartment of Biomedical EngineeringUniversity of California-DavisDavis. California

Emeritus Professor of Medical PhysicsUniversity of Wisconsin-MadisonMadison, Wisconsin

Most of the naturally occurring radio-nuclides are very long-lived (e.g., 4oK, T1/2 ~109 years) and/or represent very heavyelements (e.g., uranium and radium) thatare unimportant in metabolic or physiologicprocesses. Some of the first applications ofradioactivity for medical tracer studies in the1920s and 1930s made use of natural radio-nuclides; however, because of their generallyunfavorable characteristics indicated above,they have found virtually no use in medicaldiagnosis since that time. The radionuclidesused in modern nuclear medicine all are ofthe manufactured or "artificial" variety.They are made by bombarding nuclei ofstable atoms with subnuclear particles (suchas neutrons and protons) so as to causenuclear reactions that convert a stablenucleus into an unstable (radioactive) one.This chapter describes the methods used toproduce radionuclides for nuclear medicineas well as some considerations in the labelingof biologically relevant compounds to formradiopharmaceuticals.

continuing importance for this application,a brief description of their basic principles ispresented.

The "core" of a nuclear reactor contains aquantity of fissionable material, typicallynatural uranium (235U and 238U) enrichedin 235U content. Uranium-235 undergoesspontaneous nuclear fission (T1/2 '" 7 X 108

years), splitting into two lighter nuclearfragments and emitting two or three fissionneutrons in the process (see Chapter 3,Section I). Spontaneous fission of 235U is nota significant source of neutrons or energy ofitself; however, the fission neutrons emittedstimulate additional fission events when theybombard 235U and 238U nuclei. The mostimportant reaction is

235U + n ~236U* (5-1)

Reactor- ProducedRadionuclides

The 236U* nucleus is highly unstable andpromptly undergoes nuclear fission, releas-ing additional fission neutrons. In thenuclear reactor, the objective is to have thefission neutrons emitted in each sponta-neous or stimulated fission event stimulate,on the average, one additional fission event.This establishes a controlled, self-sustaining,nuclear chain reaction.

Figure 5-1 is a schematic representa-tion of a nuclear reactor core. "Fuel cells"containing fissionable material-e.g., ura-nium-are surrounded by a moderator mate-rial. The purpose of the moderator is to slow

1. Reactor Principles

Nuclear reactors have for many years pro-vided large quantities of radionuclides fornuclear medicine. Because of their long and

A~

46 . . . PHYSICS IN NUCLEAR MEDICINE

/COOlant

Controlrods

--Coolant out

ModeratorPneumatic line for

+- insertion andremoval of samples

+-Coolant inPressure

vessel

Uranium fuel -Shielding

Figure 5-1. Schematic representation of a nuclear reactor.

of which is dissipated ultimately as thermalenergy. This energy can be used as athermal power source in reactors. Someradionuclides can be produced directly inthe fission process and are subsequentlyextracted by chemical separation from thefission fragments. A second method forproducing radionuclides uses the largeneutron flux in the reactor to activatesamples situated around the reactor core.Pneumatic lines are used for the insertionand removal of samples. The method ofchoice largely depends on yield of thedesired radionuclide, whether suitablesample materials are available for neutronactivation, the desired specific activity, andcost considerations.

2. Fission Fragments

The fission process that takes place in areactor can lead to useful quantities ofmedically important radionuclides such as99Mo (the parent material in the 99mTcgenerator, see Section C). As describedearlier, 236U* promptly decays by splittinginto two fragments. A typical fission reac-tion is

down the rather energetic fission neutrons.Slow neutrons (also called thermal neutrons)are more efficient initiators of additionalfission events. Commonly used moderatorsare "heavy water" [containing deuterium(D2O)] and graphite. Control rods are posi-tioned to either expose or shield the fuel cellsfrom one another. The control rods containmaterials that are strong neutron absorbersbut that do not themselves undergo nuclearfission (e.g., cadmium or boron). The fuelcells and control rods are positioned care-fully so as to establish the critical conditionsfor a controlled chain reaction. If the controlrods were removed (or incorrectly posi-tioned), conditions would exist whereineach fission event would stimulate morethan one additional nuclear fission. Thiscould lead to a runaway reaction and toa possible "meltdown" of the reactor core.(This sequence occurs in a very rapid timescale in nuclear explosives. Fortunately, thecritical conditions of a nuclear explosioncannot be achieved in a nuclear reactor.)Insertion of additional control rods results inexcess absorption of neutrons and termi-nates the chain reaction. This procedure isused to shut down the reactor.

Each nuclear fission event results in therelease of a substantial amount of energy(200-300 MeV per fission fragment), most

235U+ n -+236U* -+144Ba + 89Kr + 3n (5-2 )92 92 56 36

Chapter 5: Radionuclide and Radiopharmaceutical Production 8 8 8 47

More than 100 nuclides representing 20different elements are found among thefission products of 236U*. The mass distribu-tion of the fission fragments is shown inFigure 5-2. It can be seen that fission of236U* generally leads to one fragment witha mass number in the range of 85 to 105 andthe other fragment with a mass number inthe range of 130 to 150. It also is apparentthat fission rarely results in fragments withnearly equal masses.

The fission products always have anexcess of neutrons and hence undergofurther radioactive decay by 13- emission,until a stable nuclide is reached. If one of theradioactive intermediates has a sufficientlylong half-life, it can be extracted from thefission products and used as a medicalradionuclide. For example,

99y ~-(1.5 s) 99Z39 ~ 40 r

P-(15 s) 99Mo~ 42

(5-3)

The half-life of 99Mo is 65.9 hours, which issufficiently long to allow it to be chemicallyseparated from other fission fragments.Molybdenum-99 plays an important rolein nuclear medicine as the parent radio-nuclide in the 99Mo-99mTc generator (SectionC). Technetium-99m is the most common

radionuclide used in clinical nuclear medi-cine procedures today. Fission has also beenused to produce 1311 and 133Xe for nuclearmedicine studies.

Radionuclides produced by the fissionprocess have the following general charac-teristics:

1. Fission products always have an excess ofneutrons, because N/Z is substantiallyhigher for 235U than it is for nuclei fallingin the mass range of the fission frag-ments, even after the fission productshave expelled a few neutrons (Fig. 2-8).These radionuclides therefore tend todecay by ~- emission. ' .

2. Fission products may be carrier-free (nostable isotope of the element of interest isproduced), and therefore radionuclidescan be produced with high specific activ-ity by chemical separation. (Sometimes,other isotopes of the element of interestare also produced in the fission frag-ments. For example, high-specific-activity1311 cannot be produced through fissionbecause of significant contamination from1271 and 1291.)

3. The lack of specificity of the fissionprocess is a drawback that results ina relatively low yield of the radionuclideof interest among a large amount of otherradionuclideR.


3. Neutron Activation

Neutrons carry no net electrical charge.Thus they are neither attracted nor repelledby atomic nuclei. When neutrons (e.g., froma nuclear reactor core) strike a target, someof the neutrons are "captured" by nuclei ofthe target atoms. A target nucleus may beconverted into a radioactive product nucleusas a result. Such an event is called neutronactivation. Two types of reactions commonlyoccur.

In an (n,yJ reaction a target nucleus, tx,captures a neutron and is converted intoa product nucleus, A+iX*, which is formed inan excited state. The product nucleus imme-diately undergoes de-excitation to its groundstate by emitting a prompt y ray. Thereaction is represented schematically as

~X(n,y)A+~X (5-4)

Note that the target and product nuclei foran (n,p) reaction do not represent the samechemical element.

In the earlier examples, the products(A+ix or z-1Y) usually are radioactivespecies. The quantity of radioactivity that isproduced by neutron activation dependson a number of factors, including theintensity of the neutron flux and the neutronenergies. This is discussed in detail inSection D. Production methods for bio-medically important radionuclides producedby neutron activation are summarized inTable 5-1.

Radionuclides produced by neutron acti-vation have the following general character-istics:

1. Because neutrons are added to thenucleus, the products of neutron activa-tion generally lie above the line ofstability (Fig. 2-8). Therefore, they tendto decay by (3- emission.

2. The most common production mode is bythe (n, y) reaction, and the products ofthis reaction are not carrier-free becausethey are the same chemical element as thebombarded target material. It is possibleto produce carrier-free products in areactor by using the (n,p) reaction (e.g.,32p from 32S) or by activating a short-lived intermediate product, such as 1311

The target and product nuclei of this reac-tion represent different isotopes of the samechemical element.

A second type of reaction is the (n,p)reaction. In this case, the target nucleuscaptures a neutron and promptly ejectsa proton. This reaction is represented as

~X(n,p)z-ty (5-5)

-O"c(b)tDecay

Mode

--

Production ReactionRadlonucllde NaturalAbundance ofTarget Isotope (%)*

14N(n,pr4c23Na(n,y)24Na

31P(n,y)32p32S(n,p)32p35Cl(n,p)35S41K(n,y)42K

50Cr(n,y)51Cr58Fe(n,y)5~e74Se(n,y)75Se

124Xe(n, yy25Xe ~ 125111-

130Te(n, y)131Te -+ 1311

99.610010095.075.86.74.30.30.9

0.1

33.8

1.810.530.19

14C

24Na

32p

(3-«(3-,y)

(3-

(3-«(3-,y)(EC,y)«(3-,y)(EC,y)

(EC,y)

«(3-,y)

35842K51Cr5~e758e

1251

1311

1.2

17

1.1

30

110

0.24

.Values from Browne E, Firestone RB: Table of Radioactive Isotopes. New York, John Wiley, 1986!tThermal neutron capture cross section, in barns (b), for (n,y) reactions (see Section D.O. Values from Radiological Health

Handbook. Rockville, MD, US Department of Health, Education, and Welfare, 1970, pp. 231-380.2EC, electron capture.

Chapter 5: Radionuc/ide and Radiopharmaceutical Production 8 8 8 49

from 131Te using the reaction such as protons, deuterons (~H nuclei), andcx particles (~He nuclei), to very high ener-gies. When directed onto a target material,these particles may cause nuclear reactionsthat result in the formation of radionuclidesin a manner similar to neutron activation ina reactor. A major difference is that theparticles must have very high energies,typically 10-20 MeV, to penetrate the repul-sive coulomb forces surrounding the nucleus.Van de Graaff accelerators, linear accelera-tors, cyclotrons, and variations of cyclotronshave been used to accelerate charged parti-cles. The cyclotron is the most widely usedform of particle accelerator for productionof medically important radionuclides, al-though recent designs of compact linearaccelerators also show promise.3 Manylarger institutions have now installed theirown compact biomedical cyclotrons for on-site production of the shorter-lived positron-emitting radionuclides. The principles anddesign of cyclotrons dedicated to productionof radionuclides for nuclear medicine aredescribed briefly.

13-130Te(n, y)131Te ~ 1311 (5-6)

3. Even in intense neutron fluxes, onlya very small percentage of the targetnuclei actually are activated, typically1:106 to 109 (Section D). Thus an (n,r)product may have very low specific activ-ity because of the overwhelming presenceof a large amount of unactivated stablecarrier (target material).

There are a few examples of the produc-tion of electron capture (EC) decay or~+ -emitting radionuclides with a nuclearreactor, for example, 51Cr by (n,r) activationof 50Cr. They may also be produced by usingmore complicated production techniques. Anexample is the production of 18F ([3+, T1/2=110 min). The target material is lithiumcarbonate (Li2COg). The first step is thereaction

6Li (n,y)7Li (5- 7)

2. Cyclotron Principles

A cyclotron consists of a pair of hollow,semicircular metal electrodes (called "dees"because of their shape), positioned betweenthe poles of a large electromagnet (Fig. 5-3).The dees are separated from one another bya narrow gap. Near the center of the dees isan ion source S, (typically an electrical arcdevice in a gas) that is used to generate thecharged particles. All these components arecontained in a vacuum tank at ""'10-,-3 Pa.

During operation, particles are gener-ated in bursts by the ion source, and a high-frequency alternating current (AC) voltagegenerated by a high-frequency oscillator(typically 30 kV, 25-30 MHz) is appliedacross the dees. The particles are injectedinto the gap and immediately are acceleratedtoward one of the dees by the electrical fieldgenerated by the applied AC voltage. Insidethe dee there is no electrical field, butbecause the particles are in a magneticfield, they follow a curved, circular patharound to the opposite side of the dee. TheAC voltage frequency is such that theparticles arrive at the gap just as the voltage

~Li -+ ~He +~H + energy (5-8)

Some of the energetic recoiling tritiumnuclei (~H) bombard stable 160 nuclei,causing the reaction

160 (3H n ) 18F8 1 , 9 (5-9)

Useful quantities of 18F can be produced inthis way. One problem is removal from theproduct (by chemical means) of the rathersubstantial quantity of radioactive tritiumthat is formed in the reaction. More satisfac-tory methods for producing 18F involve theuse of charged particle accelerators, asdiscussed in Section B.

Accelerator- ProducedRadionuclides

1. Charged-Particle Accelerators

Charged-particle accelerators are used toaccelerate electrically charged particles,

Lithium-7 is very unstable and promptlydisintegrates


"Dees"

Vacuum

Electrostaticdeflector

~ - Target "Dees"

Figure 5-3. Schematic representation of a positive ion cyclotron: top aeft) and side (right) views. The acceleratingvoltage is applied by a high-frequency oscillator to the two "dees." S is a source of positive ions.

The energy of particles accelerated ina cyclotron is given by

E (MeV) ~ 4.8 x 10-3 (H x R x Z)2 fA

(5-10)

where H is the magnetic field strength intesla, R is the radius of the particle orbit incm, and Z and A are the atomic number(charge) and mass number of the acceleratedparticles, respectively. The energies that canbe achieved are limited by the magnetic fieldstrength and the dee size. In a typicalbiomedical cyclotron with magnetic fieldstrength 1.5 tesla and a dee diameter of76 cm, protons (Z = 1, A = 1) and cx particles(Z =2, A = 4) can be accelerated to about15 MeV and deuterons (Z = 1, A = 2) to about8 MeV.

When the particles reach the maximumorbital radius allowed within the cyclotrondees, they may be directed onto a targetplaced directly in the orbiting beam path(internal beam irradiation). More commonly,the beam is extracted from the cyclotron anddirected onto an external target (externalbeam radiation). Typical beam currents atthe target are in the range of 50-100 ~.For cyclotrons using positively charged par-ticles (positive ion cyclotron), the beam iselectrostatically deflected by a negativelycharged plate and directed to the target(see Fig. 5-3). Unfortunately electrostaticdeflectors are relatively inefficient, as muchas 30% of the beam current being lost duringextraction. This "lost" beam activates theinternal parts of the cyclotron, thus making

across the dees reaches its maximum value(30 kV) in the opposite direction. Theparticles are accelerated across the gap,gaining about 30 keY of energy in theprocess, and then continue on a circularpath within the opposite dee.

Each time the particles cross the gap theygain energy, so the orbital radius continu-ously increases and the particles follow anoutwardly spiraling path. The increasingspeed of the particles exactly compensatesfor the increasing distance traveled per halforbit, and they continue to arrive back at thegap exactly in phase with the AC voltage.This condition applies so long as the charge-to-mass ratio of the accelerated particlesremains constant. Because of their largerelativistic mass increase, even at relativelylow energies ("-'100 keY), it is not practical toaccelerate electrons in a cyclotron. Protonscan be accelerated to 20-30 MeV, and heavierparticles can be accelerated to even higherenergies (in proportion to their rest mass),before relativistic mass changes becomelimiting. *

Higher particle energies can be achievedin a variation of the cyclotron called thesynchrocyclotron or synchrotron, in whichthe AC voltage frequency changes as theparticles spiral outward and gain energy.These machines are used in high-energynuclear physics research.

*Even at low energies, protons, deuterons, and(X particles gain some mass when accelerated ina cyclotron. Magnetic "field shaping" is used in thecyclotron to compensate for this effect.

Chapter 5: Radionuc/ide and Radiopharmaceutical Production - - - 51

unstable nature of the H- ion, the mostcommonly used particle in negative ioncyclotrons.

servicing and maintenance of the cyclotrondifficult.

In a negative ion cyclotron, negativelycharged ions (e.g. H-, a proton plus twoelectrons) are generated and then acceler-ated in the same manner as the positive ionsin a positive ion cyclotron (but in theopposite direction due to the different polar-ity). When the negatively charged ions reachthe outermost orbit within the dee elec-trodes, they are passed through a thin(5-25 ~m) carbon foil, which strips off theelectrons and converts the charge on theparticle from negative to positive. The inter-action of the magnetic beam with thispositive ion bends its direction of motionoutward and onto the target (Fig. 5-4). Thenegative ion cyclotron has a beam extractionefficiency close to 100% and can therefore bedescribed as a "cold" machine that requiresminimal levels of shielding. Furthermore,two beams can be extracted simultaneouslyby positioning a carbon stripping foil partway into the path of the beam, such that onlya portion of the beam is extracted to a target.The remainder of the beam is allowed tocontinue to orbit and is then extracted witha second stripping foil onto a different target(Fig. 5-4). This allows two different radio-nuclides to be prepared simultaneously. Onedisadvantage of negative ion cyclotrons is therequirement for a much higher vacuum(typically 10-5 Pa compared with 10-3 Pafor positive ion machines) because of the

3. Cyclotron-ProducedRadionuclides

Cyclotrons are used to produce a variety ofradionuclides for nuclear medicine, some ofwhich are listed in Table 5-2. Generalcharacteristics of cyclotron-produced 'radio-nuclides include the following:

1. Positive charge is added to the nucleus inmost activation processes. Therefore, theproducts lie below the line of stability (seeFig. 2-8) and tend to decay by EC or~+ emission.

2. Addition of positive charge to the nucleuschanges its atomic number. Therefore,cyclotron-activation products usually arecarrier-free.

3. Cyclotrons generally produce smallerquantities of radioactivity than areobtained from nuclear reactors. In partthis results from generally smaller activa-tion cross sections for charged particles ascompared to neutron irradiation (seeSection D) and in part from lower beamintensities obtained in cyclotrons as com-pared to nuclear reactors. Thus whenobtained from commercial suppliers,cyclotron products tend to be moreexpensive than reactor products.

H-

Strippingfoil

Strippingfoil

To target" "'"v ~ H- Target~

To secondstripping foil Figure 5-4. Left, Schematic representation of a negative ion cyclotron. The carbon stripping foils remove two

electrons from negative hydrogen (H-) ions, converting them into protons (p+) that bend in the opposite direction inthe applied magnetic field. Right, The first stripping foil intersects only part of the beam, allowing two beams to beextracted simultaneously.


distribution centers and shipped to hospitalstens or even hundreds of miles away. FDG isthe most widely used positron-emitting radio-pharmaceutical with a wide range of clinicalapplications in the heart and brain and incancer.

Radionuclide Generators

A radionuclide generator consists of a parent-daughter radionuclide pair contained in anapparatus that permits separation andextraction of the daughter from the parent.The daughter product activity is replenishedcontinuously by decay of the parent and maybe extracted repeatedly.

Table 5-3 lists some radionuclide gen-erators of interest to nuclear medicine.They are an important source of meta-stable radionuclides. The most importantgenerator is the 99Mo-99mTc system,because of the widespread use of 99mTcfor radionuclide imaging. Technetium-99memits y rays (140 keY) that are veryfavorable for use with a gamma camera(Chapter 13). It has a reasonable half-life(6 hours), delivers a relatively low radiationdose per emitted y ray (Chapter 21), andcan be used to label a wide variety ofimaging agents. More than 1850 'I'Rn

Cyclotron products are attractive fornuclear medicine imaging studies because ofthe high photon/particle emission ratios thatare obtained in 13+ and EC decay. Of specialinterest are the short-lived positron emittersllC (T1/2 = 20 min), 13N (T1/2 = 10 min), and150 (T 1/2 = 2 min). These radionuclides repre-sent elements that are important constitu-ents of all biologic substances, and they canbe used to label a wide variety of biologicallyrelevant tracers. Because of their very shortlifetimes, these positron-emitting radio-nuclides must be prepared on site with adedicated biomedical cyclotron. The high costof owning and operating such machines hasimpeded their widespread use. Nevertheless,because of the importance of several positron-emitter-labeled radiopharmaceuticals, thereare now more than 175 cyclotrons in hospitalsworldwide producing short-lived positron-emitting isotopes for nuclear medicine imag-ing studies. A typical biomedical cyclotron isshown in Figure 5-5.

Fluorine-IS (T1/2 = 110 min) is anotherimportant positron-emitting radionuclide.One of its main applications is in the labelingof a glucose analog, 18F -fluorodeoxyglucose(FDG), which provides a measure of themetabolic rate for glucose in the cells of thebody. The longer half-life of the 18F labelallows FDG to be produced in regional

Chapter 5: Radionuclide and Radiopharmaceutical Production. . . 53

Figure 5-5. Example of amodern negative ion biomedicalcyclotron. (Courtesy of CTIMolecular Imaging Inc.,Knoxville, TN.)

(50,000 Ci) of 99Mo per week are requiredto meet the worldwide requirements fornuclear medicine procedures.

A 99Mo_99mTc generator is shown inFigure 5-6. The parent 99Mo activity in theform of molybdate ion, MoO~- is bound to analumina (Al2Oa) column. The daughter 99mTcactivity, produced in the form of 99mTcO"i(pertechnetate), is not as strongly bound toalumina and is eluted from the column with5 to 25 mL of normal saline. Typically, 75% to85% of the available 99mTc activity isextracted in a single elution. Technetium-99m activity builds up again after an elution,and maximum activity is available about24 hours later (see Equation 4-28); however,usable quantities of 99mTc are available 3 to

Daughter. DecayMode

T1/2 Parent T1/2

-62CU66Ga82Rb87mSr99mTc113mln

9.7 mill68 mill1.3 mill2.8 hr6 hr100 mill

-62Zn66Ge82Sr87y

~O113Sn

6 hours later. Figure 5-7 shows the pattern ofactivity available in a 99mTc generator that iseluted at various intervals.

Commercially prepared generators aresterilized, well shielded, and largely auto-mated in operation. Typically they are usedfor about 1 week and then discarded becauseof natural decay of the 99Mo parent.

Molybdenum-99 activity is obtained byseparation from reactor fission fragments orby (n,r) activation of stable molybdenum(23.8% 98Mo). The former, sometimes called"fission moly," has significantly higherspecific activity and is currently the produc-tion method of choice. The v()lum~ ofalumina required in a 99Mo-99mTc generatoris determined essentially by the amount ofstable 99Mo carrier that is present.Therefore, "fission moly" generators requiremuch smaller volumes of alumina per unit of99Mo activity. They can be eluted with verysmall volumes of normal saline (~5 mL),which is useful in some dynamic imagingstudies requiring bolus injections of verysmall volumes of high activity (740 MBq,20 mCi) of 99mTc.

One problem with 99mTc generators is99Mo "breakthrough," that is, partial elutionof the 99Mo parent along with 99mTc from thegenerator. From the standpoint of patientradiation safety, the amount of 9~Oshould be kept to a miniJ;num. Maximumamounts, according to Nuclear Regulatory

'Generator product.EC, electron capture.IT. isomeric transition

9.3hr275 d25 d80 hr66 hr120 d


Figure 5-6. Cut-away view of a ~o-99mTcgenerator. (Adapted from "A Guide toRadiopharmaceutical Quality Control."Billerica, MA, Du Pont Company, 1985.)

Commission regulations, are 0.15 Bq 99Moper kBq 99mTc (0.15 ~Ci 99Mo per mCi 99mTc).It is possible to assay 99Mo activity in thepresence of much larger 99mTc activity usingNaI(TI) counting systems (Chapter 12) bysurrounding the sample with about 3 mm of

lead, which is an efficient absorber of the 140keY y rays of 99mTc but relatively transpar-ent to the 740-780 keY y rays of 99Mo. Thussmall quantities of 99Mo can be detected inthe presence of much larger amounts of99mTc. Some dose calibrators are provided

Figure 5-7. Buildup and decay of a99ffiTc generator eluted at 24, 30, 48, and96 hours.


with a lead-lined container called a "molyshield" specifically for this purpose. Otherradioactive contaminants also are occasion-ally found in 99Mo-99mTc generator eluate.

A second major concern is breakthroughof aluminum ion, which interferes withlabeling processes and also can cause clump-ing of red blood cells and possible micro-emboli. Maximum permissible levels are10 ~g/mL of 99mTc solution. Chemical testkits are available from generator manu-facturers to test for the presence of alumi-num ion.

Systeme International (SI) units for 0" arem2. The traditional and more commonlyused unit is the barn (1 b = 10-28 m2)or millibarn (1 mb = 10-3b = 10-31m2).Activation cross sections for a particularnucleus depend on the type of bombardingparticle, the particular reaction involved,and the energy of the bombarding particles.Figure 5-8 shows the activation crosssection for the production of 18F from the180(p,n)18F reaction.

Because of their importance in radio-nuclide production by nuclear reactors,activation cross sections for thermal neu-trons have been measured in some detail.These are called neutron-capture crosssections, symbolized by O"c. Some valuesof o"c of interest for radionuclide produc-tion in nuclear medicine are listed inTable 5-1.

Equations for RadionuclideProduction

1. Activation Cross Sections

The amount of activity produced whena sample is irradiated in a particle beamdepends on the intensity of the particlebeam, the number of target nuclei in thesample, and the probability that a bom-bardtng particle will interact with a targetnucleus. The probability of interaction isdetermined by the activation cross section.The activation cross section is the effective"target area" presented by a target nucleusto a bombarding particle. It has dimensionsof area and is symbolized by 0" . The

2. Activation Rates

Suppose a sample containing n targetnuclei per cm3, each having an activationcross section cr, is irradiated in a beamhaving a flux density 4> (particles/cm2.sec)(Fig. 5-9). It is assumed that the samplethickness f!J.:x (cm) is sufficiently thin that 4>

does not change much as the beam passesthrough it. The total number of targets,per cm2 of beam area, is n~x. They present

Figure 5-8. Activation cross sectionversus particle energy for the reac-tion lS0(p,n)lSF. The energy thresh-old for this reaction is 2.5 MeV.(From Ruth TJ, Wolf AP: Absolutecross sections for the productionof lsF via the lS0(p,n)lSF reaction.~Drl;~h;~;~D A~j-D ?A.?1_?A 1Q7Q)


Target material

"area, 1 cm2

. ~. ~

. ~. ~

. ~Figure 5-9. Activation targets in a parti-cle beam.

. .Target nuclei

"area, a cm2. ~

Particle beam,flux density $

-I I-dX

a total area ncr~ per cm2 of beamarea. The reduction of beam flux inpassing through the target thickness dx istherefore

Example 5- 7What is the activation rate per gram ofsodium for the reaction 23Na(n,y)24Nain a reactor thermal neutron fluxdensity of 1013 neutrons/cm2.sec?

(5-11)L\<I>/<I> = n cr L\x

The number of particles removed from thebeam (i.e., the number of nuclei activated)per cm2 of beam area per second is

(5-12)~<t>=ncr<t>Ll.x

Each atom of target material has mass A W /(6.023 X 1023) g, where AW is its atomicweight and 6.023 x 1023 is Avogadro'snumber. The total mass m of targetmaterial per cm2 in the beam is therefore

AnswerFrom Table 5-1, the thermal neutroncapture cross section for 23Na isO"c = 0.53 b. The atomic weight ofsodium is approximately 23. Therefore(Equation 5-15)

R ~ (6.023 X 1023) x (0.53 X 10-24)

x 1013/23

~ 1.38 x 1011activations/g. sec

Equation 5-15 and Example 5-1 describesituations in which the isotope representedby the target nucleus is 100% abundant in theirradiated sample (e.g., naturally occurringsodium is 100% 23Na). When the target is not100% abundant, then the activation rate pergram of irradiated element is decreased by thepercentage abundance of the isotope of inter-est in the irradiated material.

m ~ n x ~ x AW /(6.023 X 1023) (5-13)

and the activation rate R per unit mass oftarget material is thus

R ~ L\<t>/m (5-14)

R ~ (6.023 X 1023) X 0" X <I>

AW

(aetivationsjg. see) (5-15) Example 5-2Potassium 42 is produced by the reac-tion 41 K(n, y)42K. Naturally occurringpotassium contains 6.8% 41 K and 93.2%

39K. What is the activation rate of 42K

Equation 5-15 can be used to calculatethe rate at which target nuclei are activatedin a particle beam per gram of targetmaterial in the beam.


per gram of K in a reactor with thermalneutron flux density 1013 neutrons/cm2,sec?

is just equal to R, the activation rate pergram, so the saturation specific activity As is

As (Bqjg) = R (5-16)

which when combined with Equation 5-15yields

AnswerFrom Table 5-1, the neutron capturecross section Of41K is 1.2 b. The atomicweight of 41K is approximately 41.Thus (Equation 5-15)

As (Bq/g) ~ 0.6023 x a x c/>/AW (5-17)

where cr is the activation cross section inbarns, <I> is the flux in units of particles percm2.sec, and AW is the atomic weight of thetarget material. The final equation forspecific activity versus irradiation time is

R ~ (6.023 X 1023) X (1.2 X 10-24)

X 1013/41

~ 1.76 X 1011 activations/g(41K). see

At (Bqjg) =As (l-e-At) (5-18)The activation rate per gram of potas-sium is 6.8% of this, that is,

where A is the decay constant of the product(compare with Equation 4-26). The specificactivity of the target reaches 50% of thesaturation level after irradiating for onedaughter product half-life, 75% after twohalf-lives, and so on (see Fig. 4-7). No matterhow long the irradiation, the sample specificactivity cannot exceed the saturation level.Therefore, it is unproductive to irradiatea target for longer than about three or fourtimes the product half-life.

R ~ 0.068 x (1.76 x 1011)

~ 1.20 X 1010 activationsjg(K) . see

Activation rates are less than predictedby Equation 5-15 when the target thickness issuch that there is significant attenuation ofparticle beam intensity as it passes throughthe target (i.e., some parts of the target areirradiated by a weaker flux density). Also,when "thick" targets are irradiated bycharged-particle beams, the particles loseenergy and activation cross sections changeas the beam penetrates the target. The equa-tions for these conditions are beyond thescope of this book and are discussed inreference 4.

Example 5-3

What is the saturation specific activityfor the 42K production problemdescribed in Example 5-2? Comparethis to the carrier-free specific activity(CFSA) of 42K (the half-life of 42K is12.4 hours).3. Buildup and Decay of Activity

When a sample is irradiated in a particlebeam, the buildup and decay of productradioactivity is exactly analogous to a specialcase of parent-daughter radioactive decaydiscussed in Chapter 4, Section G .2. Theirradiating beam acts as an inexhaustible,long-lived "parent," generating "daughter"nuclei at a constant rate. Thus, as shown inFigure 4-7, the product activity starts fromzero and increases with irradiation time,gradually approaching a saturation levelat which its disintegration rate equalsits production rate. The saturation levelcan be determined from Equation 5-15.The saturation disintegration rate per gram

AnswerApplying Equation 5-17 with cr = 1.2 b,cf>= 1013, and AW ~ 41,

As = 0.6023 x 1.2 x 1013/41=1.76 x 1011(Bq 42K/g 41 K)

If natural potassium is used, only 6.8%is 41 K. Therefore, the saturation spe-

cific activity is

As =(1.76 x 1011) X 0.068

=1.20 x 1010 Bq 42K/g K


A' = 0.693 x (1.20 x 101°)/12.4

~ 6.7 x 108 Bq 42K/g K. hr

The CFSA of 42K (T1/2 '" 0.5 days) is(Equation 4-21)

CFSA ~ (4.8 x 1018)/(41 x 0.5)

~2.3 x 1017Bq 42K/g 42K After 3 hours, which is "short" incomparison to the half-life of 42K, thespecific activity of the target is(Equation 5-20)

A(Bqjg) ~ (6.7 x 108) X 3

~2.0 X 109 Bq 42Kjg K

Example 5-3 illustrates the relativelylow specific activity that typically is obtainedby (n,y) activation procedures in a nuclearreactor.

A parameter that is related directly to thesaturation activity in an activation problemis the production rate, A'. This is the rate atwhich radioactivity is produced during anirradiation, disregarding the simultaneousdecay of radioactivity that occurs during theirradiation. It is the slope of the productioncurve at time t = 0 (before any of thegenerated activity has had opportunity todecay). The production rate can be shown bymethods of differential calculus to be equal to

Radionuclides for NuclearMedicine

1. General Considerations

A'(Bqjg. hr) = In2 x As (Bqjg)jT1/2(hr)

(5-19)

where T1/2 is the half-life of the product.Reactor production capabilities may be

defined in terms of either saturation levels orproduction rates. If the irradiation time t is"short" in comparison to the product half-life, one can approximate the activity pro-duced from the production rate according to

(5-20)

In elemental form, radionuclides generallyhave a relatively small range of biologicallyinteresting properties. For example, 1311 asan iodide ion (I-) is useful for studying theuptake of elemental iodine in the thyroid orin metastatic thyroid cancer or for deliveringa concentrated radiation dose to thyroidtissues for therapeutic purposes; however,elemental iodine has no other generallyinteresting properties for medical usage.For this reason, most studies in nuclearmedicine employ radio pharmaceuticals, inwhich the radionuclide is attached as a labelto a compound that has useful biomedicalproperties.

For most applications, the radiopharma-ceutical is injected into the patient, and theemissions are detected using external ima-ging or counting systems. Certain practicalrequirements must be met for a radionuclideto be a useful label. A portion of the Chartof Nuclides was shown in Figure 3-11. Acomplete chart contains hundreds of radio-nuclides that could conceivably be used forsome biomedical application, either in ele-mental form or as a radiopharmaceuticallabel. However, the number of radionuclidesactually used is much smaller because ofvarious practical considerations, as discussedin the following section. A listing of some ofthe more commonly used radionuclides fornuclear medicine procedures is presented inTable 5-4.

At (Bqjg) ~ A' x t

~ In 2 x As x tjT1/2 (5-21)

where t and T 1{2 must be in the same units.

Example 5-4

What is the production rate of 42K forthe problem described in Example 5-2,and what specific activity would beavailable after an irradiation period of3 hours? (The half-life of 42K is 12.4hours.)

AnswerFrom Example 5-3, As = 1.20 X 1010 Bq42K!g K. Therefore (Equation 5-19)

Chapter 5: Radionuclide and Radiooharmaceutical Production. . . 59

-11C13N15018F32p67Ga82Rb89Sr99mTc1111n

1231

1251

1311

153Sm

186Re201T1

511 keY511 keY511 keY511 keY

93, 185, 300 keY511 keY

140 keY172,247 keY

159 keY27-30 keY x rays

364 keY41, 103 keY

137 keY68-80 keY x rays

20.3 mill10.0 min2.07 min110 min14.3 d3.26 d1.25 min50.5 d6.03 hr2.81 d13.0 hr60.2 d8.06 d46.7 hr3.8 d!'!1Ir; ~

EC. electron caoture: IT. isomeric transition.

2. Soecific Considerations compounds such as H2150 and C150. If thehalf-life were longer, a much wider range ofcompounds could be labeled with 150. Otherradionuclides have half-lives that are toolong for practical purposes. Most of theradiation is emitted outside of the examina-tion time, which can result in a highradiation dose to the patient in relation tothe number of decays detected during thestudy. Long-lived radionuclides also cancause problems in terms of storage anddisposal. An example of a very long-livedradionuclide that is not used in humanstudies due to half-life considerations is22Na (T1/2=2.6 yr).

The specific activity of the radionuclidelargely determines the mass of a compoundthat is introduced for a given radiationdose. Since nuclear medicine relies on theuse of sub-pharmacologic tracer doses thatdo not perturb the biologic system understudy, the mass should be low and thespecific activity high. At low specific activ-ities, only a small fraction of the moleculesin the sample are radioactive and thereforesignal-producing, whereas the rest of themolecules add to the mass of the compoundbeing introduced, without producing signal.Theoretically, the attainable specific activityof a radionuclide is inversely proportional toits half-life. althoUQ"h in nractiCA. manv

The type and energy of emissions from theradionuclide determine the availability ofuseful photons or y rays for counting orimaging. For external detection of a radio-nuclide inside the body, photons or y rays inthe 50-600 keY energy range are suitable.Very low energy photons and y rays« 50 keY), or particulate radiation, havea high likelihood of interacting in the bodyand will not in general escape for externaldetection. The presence of such low energyor particulate emissions increases the radia-tion dose to the patient. An example of thiswould be 1311, which decays by (f3-,y) emit-ting a f3-, followed by y rays at 364 (82%),637 (6.5%), 284 (5.8%), or 80 keY (2.6%). They rays are in an appropriate range forexternal detection; however, the f3- contri-butes additional dose as compared withradionuclides that decay by (EC, y).

The physical half-life of the radionuclideshould be within the range of seconds to days(preferably minutes to hours) for clinicalapplications. If the half-life is too short, thereis insufficient time for preparation of theradiopharmaceutical and injection into thepatient. An example of this is the positron-emitter 150 (T1/2 = 123 sec). This limits150-labeled radiopharmaceuticals to simple


a cost (both materials and labor) consistentwith today's health care market.

As noted earlier, radionuclides almostalways are attached as labels to compoundsof biomedical interest for nuclear medicineapplications. Because of the practical con-siderations discussed in the preceding sec-tion, the number of different radionuclidesroutinely used in nuclear medicine is rela-tively small, perhaps fewer than a dozeneven in large hospitals. On the other hand,the number of labeled compounds is muchlarger and continuously growing, owing tovery active research in radiochemistryand radiopharmaceutical preparation. Thefollowing sections summarize the proper-ties of some radiopharmaceuticals thatenjoy widespread usage at this time. Moredetailed discussions are found in the arti-cles and texts listed in the Bibliography.

1. General Considerations

The final specific activity of a radiopharma-ceutical (as opposed to the radionuclide) isdetermined by losses in specific activity thatoccur during the chemical synthesis of theradiopharmaceutical. This is particularly anissue for isotopes of elements that have highnatural abundances. For example, the theo-retical maximum specific activity for llC is3.5 X 108 MBq/Jlmol (CFSA from Equation4-22), whereas the specific activity ofllC-labeled radiopharmaceuticals actuallyobtained in practice is approximately105 MBq/Jlmol. This is largely due to thepresence of stable carbon in the air (as CO2)and in the materials of the reaction vesselsand tubing used in the chemical synthesisprocedure.

Radiochemical purity is the fraction ofthe radioactivity in the sample that ispresent in the desired chemical form.Radiochemical impurities usually stem fromcompeting chemical reactions in the radio-labeling process or from decomposition(chemical or radiation induced) of thesample. Radiochemical impurities are

other factors (e.g., the abundance ofstable isotopes in air and glassware) candetermine the actual specific activity of theinjected labeled compound as described inSection F.l.

The radionuclidic purity is defined asthe fraction of the total radioactivity ina sample that is in the form of the desiredradionuclide. Radionuclidic contaminantsarise in the production of radionuclidesand can be significant in some situations.The effect of these contaminants is toincrease the radiation dose to the patient.They may also increase detector dead time,and if the energy of the emissions fallswithin the acceptance window of thedetector system, contaminants may resultin incorrect counting rate or pixel inten-sities in images. Of concern in radionuclidegenerator systems is contamination withthe long-lived parent radionuclide. In thecase of the 9~o-99mTc generator, theradionuclidic purity of the 99mTc must behigher than 99.985%, as discussed inSection C.

The chemical properties of the radio-nuclide also are an important factor.Radionuclides of elements that can easilyproduce useful precursors (chemical formsthat are readily reacted to form a widerange of labeled products) and that canundergo a wide range of chemical synthesesare preferred (e.g., 1231, 18F, and 11C).Radionuclides of elements that are easilyincorporated into biomolecules, withoutsignificantly changing their biochemicalproperties, also are attractive. Examplesare 11C, 13N, 150, elements that are foundnaturally in many biomolecules. Metalssuch as 99mTc and 67Ga also are widelyused as labels in nuclear medicine, becauseof the desirable imaging properties of theradionuclide. To incorporate such elementsinto biologically relevant molecules is chal-lenging but can be achieved by chelationand other techniques that seek to "hide"or shield the metal atom from the biologi-cally active sites of the molecule.

Finally, the cost and/or complexity ofpreparing a radionuclide must be considered.Sufficient quantities of radionuclide forradiopharmaceutical labeling and subse-quent patient injection must be produced at


2. Labeling Strategiesproblematic in that their distribution in thebody is generally different, thus addinga background to the image of the desiredcompound. Typical radiochemical purity forradiopharmaceuticals are higher than 95%.Chemical purity (the fraction of the samplethat is present in the desired chemical form)is also important, with desirable values ofgreater than 99%.

The dynamic time course of the radio-pharmaceutical in the body must be consid-ered. Some radiopharmaceuticals have rapiduptake and clearance, whereas others circu-late in blood with only slow uptake intotissues of interest. The rate of clearance ofthe radiopharmaceutical from the body iscalled the biologic half-life. Together withthe physical half-life of the radionuclide, thisdetermines the number of radioactive decaysthat will be observed from a particularregion of tissue as a function of time. Thesetwo factors also are important factors indetermining the radiation dose to the subject(see Chapter 21, Section B.1). It is importantthat radiopharmaceuticals be labeled withradionuclides with half-lives that are longenough to encompass the temporal charac-teristics of the biologic process being studied.For example, labeled antibodies generallyrequire hours to days before significantuptake in a target tissue is reached andblood levels have dropped sufficiently for thetarget to be visualized. Short-lived radio-nuclides with half-lives of minutes or lesswould not be useful in this situation.

The radiopharmaceutical must not betoxic at the mass levels administered. Thisrequirement usually is straightforward innuclear medicine studies because of therelatively high specific activity of most radio-pharmaceuticals, resulting in typical injec-tions of microgram to nanogram quantitiesof material. Generally, milligram levels ofmaterials are required for pharmacologiceffects. Safety concerns also require that allradiopharmaceuticals be sterile and pyrogen-free prior to injection. Organisms can beremoved by fIltration through a sterile filterwith a pore size of 0.22 ~m or better. Useof pharmaceutical-grade chemicals, sterilewater, and sterilized equipment can mini-mize the risk of pyrogens. Finally, the pH ofthe iniected solution should be appropriate.

There are two distinct strategies for labelingof small molecules with radionuclides. Indirect substitution, a stable atom in themolecule is replaced with a radioactive atomof the same element. The compound hasexactly the same biologic properties as theunlabeled compound. This allows many com-pounds of biologic relevance to be labeled andstudied in vivo using radioactive isotopes ofelements that are widely found in nature(e.g., hydrogen, carbon, nitrogen, andoxygen). An example would be replacinga 12C atom in glucose with a llC atom tocreate llC-glucose. This radiopharmaceuticalwill undergo the same distribution andmetabolism in the body as unlabeled glucose.The second approach is to create analogs.This involves modifying the original com-pound. Analogs allow the use of radioactiveisotopes of elements that are not so widelyfound in nature but that otherwise havebeneficial imaging properties (e.g., fluorineand iodine). Analogs also allow chemists tobeneficially change the biologic properties ofthe molecule by changing the rates of uptake,clearance, or metabolism. For example, re-placing the hydroxyl (OH) group on thesecond carbon in glucose with 18F results inFDG, an analog of glucose. This has theadvantage of putting a longer-lived radio-active tag onto glucose compared with llC;and even more important, FDG undergoesonly the first step in the metabolic pathwayfor glucose, thus making data analysis muchmore straightforward (see Chapter 20,Section E.5). FDG is now a widely used radio-pharmaceutical for measuring metabolicrates for glucose. The downside to analogsare that they behave differently from thenative compound, and these differences needto be carefully understood if the analog is usedto provide a measure of the biologic function~elated to the native molecule.

An alternative approach to labelingnaterials that is possible only for larger1iomolecules is to keep the radioactive labeliway from the biologically active site of thenolecule. Thus large molecules (e.g., anti-Jodies, peptides, and proteins) may be labe-led with many different radionuclides, withminimal effect on their biologic properties.


3. Technetium 99m-Labeled

Radiopharmaceuticals

The 99Mo-99mTc generator produces tech-netium in the form of 99mTcO4' A numberof "cold kits" are available that allowdifferent 99mTc complexes to be producedby simply mixing the 99mTcO4 and thecontents of the cold kit together. The coldkit generally contains a reducing agent,usually stannous chloride, which reducesthe 99mTc to lower oxidation states, allow-ing it to bind to a complexing agent (alsoknown as the ligand) to form theradiopharmaceutical. Using these kits, arange of 99mTc-Iabeled radiopharmaceuti-cals that are targeted to different organsystems and different biologic processes canbe prepared quickly and conveniently inthe hospital setting. Table 5-5 lists a fewexamples of 99mTc radiopharmaceuticalsthat are prepared from kits.

150 requires in-house radionuclide produc-tion in a biomedical cyclotron and rapidsynthesis techniques to incorporate theminto radiopharmaceuticals. On the otherhand, the relatively longer half-life of18F permits its distribution within a radiusof a few hundred miles from the site ofproduction, thus obviating the need ofa cyclotron in the nuclear medicine imagingfacility.

The most widely used positron-labeledradiopharmaceutical is the glucose analogFDG. Glucose is used by cells to produceadenosine triphosphate, the energy "cur-rency" of the body, and accumulation ofFDG in cells is proportional to the metabolicrate for glucose. Because the energydemands of cells are altered in many diseasestates, FDG has been shown to be a sensitivemarker for a range of clinically importantconditions, including neurodegenerative dis-eases, epilepsy, coronary artery disease, andmost cancers and their metastases.

5. Radiopharmaceuticals for

Therapy Applications

4. Radiopharmaceuticals Labeledwith Positron Emitters

Positron emitters such as 11C, 13N, and 150can be substituted for stable atoms of thesame elements in compounds of biologicimportance. This results in radiolabeledcompounds with exactly the same biochem-ical properties as the original compound.Alternatively, 18F, another positron-emittingradionuclide, can be substituted for hydro-gen to produce labeled analogs. Severalhundreds of compounds have been synthe-sized with llC, 13N, 150, or 18F labels forimaging with positron emission tomography(PET). The short half-life of llC, 13N, and

Other radiopharmaceuticals are designed fortherapy applications. These are normallylabeled with a ~- emitter, and the radio-pharmaceutical is targeted against abnormalcells, commonly cancer cells. The ~- emitterdeposits radiation only within a small radius(typically 0.1 to 1 mm) and selectively killscells in this region through radiationdamage. If the radiopharmaceutical is morereadily accumulated by cancer cells thannormal cells, a therapeutic effect can beobtained.

Chapter 5: Radionuclide and Radiopharmaceutical Production 8 8 8 63

(eds): Diagnostic Nuclear Medicine, Vol 1, 3rd ed.Baltimore, Williams & Wilkins, 1996, pp 231-249.

4. Murray RL: Nuclear Energy, 4th ed. Oxford,Pergamon Press, 1993.

6. Radiopharmaceuticals in ClinicalNuclear Medicine

Bibliography

Many different radiopharmaceuticals havebeen approved for use in clinical nuclearmedicine studies. Each of these radiopharma-ceuticals is targeted to measuring a specificbiologic process, and therefore what is mea-sured depends directly on which radiophar-maceutical is administered to the patient.Some of the more common radiopharmaceu-ticals are lIsted in Tables 1-1 and 5-5.

Most radiopharmaceuticals are used inconjunction with imaging systems that candetermine the location of the radiopharma-ceutical within the body. Often, the rate ofchange of radiopharmaceutical localizationwithin a specific tissue (the rate of uptake orclearance) is also important and is measuredby acquiring multiple images as a function oftime. The imaging systems used in nuclearmedicine studies are discussed in Chapters13 to 18.

Detailed information on radionuclide production andradiopharmaceutical preparation can be found inthe following:

Friedlander G, Kennedy JW, Macias ES, Miller JM:Nuclear and Radiochemistry, 3rd ed. New York,John Wiley, 1981.

Helus F, Colombetti LG: Radionuclide Production, VolsI, II. Boca Raton, CRC Press, 1983.

Sampson CB: Textbook of Radiopharmacy: Theory andPractice. New York, Gordon & Breach, 1990.

Biomedical cyclotrons and the production of positron-emitting radionuclides and radio pharmaceuticalsare discussed in the following:

McCarthy TJ, Welch MJ: The state of positron-emittingradionuclide production in 1997. Semin Nucl Med28:235-246, 1998.

Saba GB, MacIntyre WJ, Go RT: Cyclotrons andpositron emission tomography radiopharmaceuti-cals for clinical imaging. SelDin Nucl Med22:150-161, 1992.

Tewson TJ, Krohn KA: PET radiopharmaceuticals:State-of-the-art and future prospects. SelDin NuclMed 28:221-234, 1998.

References

1. Browne E, Firestone RB: Table of RadioactiveIsotopes. New York, John Wiley, 1986. .

2. Radiological Health Handbook. U.S. Departmentof Health, Education and Welfare, Bureau ofRadiological Health, Rockville, MD, U.S.Government Printing Office, 1970, pp 231-380.

3. Dunn BD, Manning RG: Accelerators and positronemission tomography radiopharmaceuticals. InSandler MP, Coleman RE, Wackers FJ, et al

Generator systems {or radionuclide production arediscussed in the following:

Boyd RE: Molybdenum-99: Technetium-99m generator.Radiochim Acta 30:123-145, 1982.

Knapp FF, Mirzadeh S: The continuing role of radio-nuclide generator systems for nuclear medicine.Eur J Nucl Med 21:1151-1165, 1994.

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