Cyclotrons and Positron Emission Tomography Radiopharmaceuticals for Clinical Imaging Gopal B. Saha, William J. Maclntyre, and Raymundo T. Go Positron emission tomography (PET) requires positronemitting radionuclides that emit 511-keV photons detectable by PET imagers. Positron-emitting radionuclides are commonly produced in charged particle accelerators, eg, linear accelerators or cyclotrons. The most widely available radiopharmaceuticals for PET imaging are carbon-11-, nitrogen-13-, and oxygen-15labeled compounds, many of which, either in their normal state or incorporated in other compounds, serve as physiological tracers. Other useful PET radiopharmaceuticals include fluorine-18-, bromine-75-, gallium-68 (r~Ga)-, rubidium-82 (~tRb)-, and copper-62 (S2Cu)-Iabeled compounds. Many positron emitters

have short half-lives and thus require on-site cyclotrons for application, and others (UGa, e=Rb, and SZCu) are available from radionuclide generators using relatively long-lived parent radionuclides. This review is divided into two sections: cyclotrons and PET radiopharmaceuticals for clinical imaging, in the cyclotron section, the principle of operation of the cyclotron, types of cyclotrons, medical cyclotrons, and production of radionuclides are discussed. In the section on PET radiopharmaceuticals, the synthesis and clinical use of PET radiopharmaceuticals are described. Copyright 9 1992 by W.B. Saunders Company

.O. LAWRENCE first proposed the conE cept of a cyclotron for the acceleration of charged particles in 1929 and then built and

field perpendicular to the plane of the dees will force it to move in a circular path. When the charged particle again reaches the gap, the polarity of the dees is changed, and the particle will be further accelerated towards the other dee. Now its velocity is greater than the previous value and it passes through a larger radius. The radiofrequency oscillators are tuned such that change in polarities is in phase with the arrival of charged particles at the gap. Each time the ion crosses the dee gap, it gains kinetic energy equal to the product of its charge and the voltage difference between the dees. Finally, as the ions reach the periphery, the beam is removed by an oppositely charged deflector plate and allowed through a window to be used for irradiation of targets. If an ion of mass (M) and charge (e) moves with a velocity (V) under the magnetic field (H), the centripetal force (HeV) will be equal to centrifugal force given by MVZ/r where r is the radius of the ions circular path. Thus,

reported a cyclotron in 1930 that produced 13-keV H2 § ions. The basic principle of a cyclotron involves the acceleration of charged particles, such as protons, deuterons, 3H+ +, and particles, in a circular path by the application of radiofrequency and magnetic field but without the use of high voltages. A schematic diagram of a typical cyclotron is shown in Fig 1. It consists of two hollow semicircular electrode boxes, A and B, called "dees" by reason of their shapes. The dees are placed inside an evacuated tank and are connected to a radiofrequency oscillator to supply potential so that their polarities can be alternated, ie, when one dee is positive, the other is negative) The ion source (S) is placed at the center of the gap between the two dees. Ions are normally produced by ionization of an appropriate gas using an electrical arc, such as protons from ionization of H2 gas. For example, when a positively charged particle is produced at the position S, it will be accelerated towards the negatively charged dee. Once inside the dee, it is no longer under the influence of the electrical field, but a magnetic From the Department of Nuclear Medicine, ClevelandClinic Foundation, Cleveland, OH. Address reprintrequests to GopalB. Saha, PhD, Department of Nuclear Medicine, Gb3, Cleveland Clinic Foundalion, 9500 Euclid Ave, Cleveland, OH 44195-5074. Copyright 9 1992 by W.B. Saunders Company 0001-2998/92/2203-0002505.00/0 150

MV 2 HeV -

r

(1)

This leads to the kinetic energy of the ion as 1 H2e2r 2 E=~MV z- 2M

(2)

The radiofrequency and magnetic field required for acceleration depends on the mass of the ion. As the velocity of the ion becomes high, its relativistic mass also increases, thus requiring a change in magnetic field H or frequency, Seminars in Nuclear Medicine, Vol XXII, No 3 (July), 1992: pp 150-161

CYCLOTRONS AND PET RADIOPHARMACEUTICALS

B Fig 1. Schematic diagram of a cyclotron. A and B, dees. S, ion source; D, deflector; V, alternating voltage; W, window.

which is not feasible in conventional cyclotrons. For this reason, protons in such cyclotrons cannot be accelerated to more than 20 MeV. To achieve higher energies, either the magnetic field must be increased or the radiofrequency must change as the mass of the ion increases with increasing velocity. To obtain a useful beam intensity, the motion of the particles must be confined to a horizontal plane in the center of the dees. This is accomplished by vertical focusing of the beam by proper shaping of the magnetic field. 2 Different ions of the same e/M, such as particles and deuterons, can be accelerated to the same velocity with the same radiofrequency and magnetic field. Thus, oLparticles will have twice the kinetic energy of the deuterons. On the other hand, with the same magnetic field, the deuterons will have half the kinetic energy of the protons. In order to accelerate protons to the same velocity in cyclotrons designed for deuterons, the magnetic field H is normally halved, and the proton energy is half that of the deuteronsl The reduction of the magnetic field tends to defocus the beam. MEDICAL CYCLOTRONS

Medical cyclotrons can be broadly categorized as those cyclotrons that are used for production of radionuclides primarily for medical use. These machines Can accelerate low to

151

moderate energy-charged particles. Very highenergy linear accelerators are occasionally used in the production of radionuclides for medical use; examples are the accelerators at the Brookhaven National Laboratory and the Los Alamos Scientific Laboratory. The compact cyclotrons are generally used for the production of short-lived radionuclides for positron emission tomography (PET) imaging. Over the years, several commercial vendors have marketed both low- and medium-energy cyclotrons; only the recent cyclotrons that are on the market will be briefly discussed and compared. Different medical cyclotrons supplied by various commercial firms are shown along with their specifications in Table 1. The advantage of negative-ion cyclotrons is that they do not activate the shielding material as the positive ions do, and they also require relatively less shielding material. In most cyclotrons, resistive magnets are used, whereas a superconducting magnet is employed in the cyclotron supplied by Oxford Instruments (Oxford, England). Also included in Table 1 is a linear accelerator in which positive ions are accelerated. A 3-MeV cyclotron is marketed by Ion Beam Applications to produce only oxygen-15 (150) by the (p,n) reaction on the lSN target. Many medical cyclotrons have an assembly of multiple targets so that the beam can be switched from one target to the next in a very short time. These targets are designed for production of specific radionuclides such as carbon-ll (11C), nitrogen-13 (13N), 150, and fluorine-18 (18F), which are the most common radionuclides used for PET studies. In some cyclotrons, the negative-ion beam can be split into two beams that can be used for irradiation of two targets to produce two radionuclides simultaneously. However, this reduces the yield of the radionuclides of interest for a given time of irradiation, because of the reduction in beam intensity by splitting. Weights of the magnets vary from one manufacturer to another; therefore, space requirements may vary for different cyclotrons. However, overall space requirement is affordable in a hospital setting. In the case of the cyclotron from the Oxford Instruments, the liquid helium must be replenished annually in the superconducting magnet.

152

SAHA, MACINTYRE, AND GO

Table 1. Specifications of Different Commercial Medical Cyclotrons* Available at Present Name of Company

Cyclotron

Siemens-CTI IBA

RDS-12 Cyclotron 10

Ebco Technologies, Inc Oxford Instruments Japan Steel Works, Ltd Sumitomo

TR3

Scanditronix

MC 17F

GE Medical Systems

PET-trace 200

Accelerator Applications, Inc

Tandem Cascade Electrostatic

Clinitron Baby Cyclotron Cypris Model 326

Type of Particle

Maximum Energy (MeV)

Beam Current (p.A)

HHdHdHH+ d+ H+ d+ H+ d+ HdH+ d+

12 10 5 13 8 12 12 6 15 8 17.2 8.6 16.5 8.4 3.7 3.7

30 50 50 50 50 50 60 60 50 50 65 65 50 50 75-200

No. of Targets

Beam Splittingt

Resistive Resistive

4 8

Yes (2) Yes (2)

Resistive

5

Yes (2)

Superconducting Resistive

7 6

No (1) No (1)

Resistive

8

No (1)

Resistive

1

No (1)

Resistive

6

No (1)

N/A

1

No (1)

Magnet

Abbreviation: N/A, not applicable. *Some cyclotrons are not yet installed for clinical use. tBeam splitting indicates the number or irradiations that can be made simultaneously.

Automated chemical synthesis boxes, often called "black boxes," are supplied by almost all cyclotron companies to synthesize common PET radiopharmaceuticals. These boxes contain hardware such as glassware, pipetting mechanisms, solenoids, necessary chemicals, etc, and they are operated by computer-controlled instructions. These instructions can be customdesigned to suit one's own specific synthesis. Different radiopharmaceuticals that have been synthesized by black boxes include: 11CO, 11CO2, 13NH3, 1502, H2150, C150, C1502, 18Ffluorodeoxyglucose (FDG), and lSF 3,4-dihydroxyphenylalanine. PRODUCTION OF RADIONUCLIDES

When a target is placed in the path of an accelerated charged particle beam, the incident particle strikes the target nucleus depositing all its energy into the nucleus (low-energy acceleration) and ultimately is absorbed by the target nttcleus. The excited nucleus will then emit protons and neutrons until all excitation energy is disposed of, thus producing different radionuelides. Each nuclear reaction producing a particular radionuclide has a threshold energy that must be supplied by the incident particle. Various nuclear reactions producing common PET radionuclides are given in Table 2. The yield of each radionuclide depends on the

beam intensity, the amount of target material bombarded, and the cross-section for the production of the radionuclide and time of bombardment. Other important PET radionuclides include rubidium 82 (82Rb), gallium-68 (68Ga), and copper-62 (62Cu). Rubidium-82 has a half-life (T~/2) of 75 seconds, and it is available from the strontium-82 (SZSr)/SZRb generator. Strontium-82 (T1/2 = 25 days) is produced in the high-energy accelerator by spallation reaction. Gallium-68 has a T~/2 of 68 minutes. Although it can be produced in the cyclotron, it is commonly available from the germanium-68 (68Ge)/68Ga generator. Germanium-68 (T1/2 = 270 days) is produced in the cyclotron by the 69Ga (p, 2n68Ge reaction. Copper-62 has a T1/2 of 9.8 minutes and is available from the zinc-62 (62Zn)/ 62Cu generator. Zinc-62 (T1/2 = 9.2 hours) is prottuced in the cyclotron. Table 2. Nuclear Reactions for Producing PET Radionuclides Target

Nuclear Reaction

N2 Enriched 15N O2 N2

14N (d, n) 1so ~SN (p, n) 1sO 1sO (p, r 13N 14N (p, a) 11C

Neon gas HzleO

2~ (d, ~) lSF 180 (p, n)18F

Tv2 of Nuclide (min) 2 2 10 20.4 110 110

CYCLOTRONS AND PET RADIOPHARMACEUTICALS

RADIOPHARMACEUTICALS FOR PET

Most PET radiopharmaceuticals can be classified broadly into three categories-perfusion, metabolic, and receptor binding-based on their application in the evaluation of different physiological parameters. The following discussion of PET radiopharmaceuticals will be made according to this classification. In addition, a section on miscellaneous use of PET radiopharmaceuticals will be included.

PET Radiopharmaceuticals for Perfusion Imaging Nitrogen-13ammonia. Nitrogen-13-has a T1/2 of 10 minutes and decays by positron emission. It is produced by the 160 (p,e0 13N reaction in the cyclotron. Nitrogen-13-ammonia is synthesized by reduction of [13N] nitrate in the presence of a mixture of NaOH and TIC13, and it is recovered in physiological saline. 3 13NH3 is obtained with a purity greater than 99%. Another important method for the production of 13NH3 is by deuteron irradiation of methane from which the 13NH3formed is collected in an acidic water solution. 4 The solution is then made basi c, and 13NH3is distilled into a slightly acidic solution. The radiochemical purity is approximately 97%. Phelps et al 5 studied the brain and myocardial perfusion in rhesus monkeys and humans using 13NH3 PET. In the rhesus monkey, 13NH3 is efficiently extracted by the brain and clears from it slowly (TI/2 = 60 to 70 minutes after intravenous administration). In humans, the ratio of cerebellar-to-subcortical white m a t t e r 13NH 3 uptake is about 3.3. After intravenous administration, 13NH3 circulates in the blood as 13NH4+. It is cleared rapidly from the blood and localizes primarily in the brain and myocardium. Less than 2% of the maximum activity remains in the blood at 5 minutes after administration. 6 Myocardial uptake of 13NH3 is proportional to the blood flow. The first-pass extraction is almost 100%. Diffusion of ammonia through the cell membrane and fixation by the glutamic acid-glutamine metabolic pathway define myocardial uptake. 7 Myocardial uptake was found to depend on the blood flow and metabolic status of the heart. 8 Tamaki et al9A~employed 13NI-t3 and PET imaging in patients with coro-

153

nary artery diseases (CADS) and obtained high sensitivity and accuracy in detecting CAD, even better than thallium-201 (2~ single photon emission computed tomography (SPECT)2 ~ Myocardial perfusion reserve was measured before and after percutaneous transluminal angiography in humans using 13NH3, and PET and was found to be directly proportional to improved coronary flow reserve.n Rubidium-82. Rubidium-82 decays by [3+ emission with a T1/2 of 75 seconds, and it is available from the 82Sr/82Rb generator. 12 Srontium-82 (T1/2 = 25 days) decays to 82Rb by electron capture. It is produced by spaUation reactions on molybdenum target (Los Alamos National Laboratory) or by irradiation of a rubidium target with high-energy protons (Brookhaven National Laboratory). Purified 82Sr in 100- to 150-mCi quantities is adsorbed on a hydrous tin oxide (SnO2) column. Rubidium-82 is eluted with physiological saline. Because of the short T1/2 life, 82Rb is administered to patients by an infusion pump. 13 The first-transit extraction of 82Rb by myocardium is 65% to 75% at normal blood flow. 14 Because 82Rb is a monovalent analog of K § it is taken up by the myocytes using the Na§ § adenosine triphosphatase pump mechanism. The 82Rb PET technique has been employed to detect CADs2536 In these studies, myocardial stress is induced by dipyridamole infusion and handgrip exercise. Gould et a115obtained a good correlation between 82Rb PET and coronary arteriography in the detection of myocardial perfusion defects. Go et a116 reported a higher sensitivity and comparable specificity for 82Rb PET compared with 2~ SPECT. Myocardial blood flow was measured using 82Rb and PET under different metabolic and pharmacological conditions27 The values correlated well with those obtained by the microsphere technique. Drugs such as glucoseinsulin, digoxin, and propranolol did not affect the myocardial uptake. In the study by Wilson et al, 18 regional myocardial extraction was found to be inversely proportional to blood flow to the region, and prolonged abnormalities in the 82Rb uptake and extraction occur in myocardium recovering from transient ischemia. Oxygen-15 water. Oxygen-15 has a T1/2 of 2 minutes and decays by positron emission. The

154

150 radionuclide produced in the cyclotron is passed over activated charcoal heated at 400 ~ to 600~ to convert it to CO150. Oxygen-15 water is prepared by bubbling CO150 into water 19 or by the direct reaction of aso z with hydrogen gas. 20 Several investigators zv25 reported the measurement of cerebral blood flow (CBF) using H2150 PET imaging in humans. Brain blood flow was measured by Herscovitch et a121 and Raichle et a122in animals using the H2150 PET and autoradiographic techniques. In the flow range of 10 to 63 mL/min/100 g, CBF (PET) = 0.90 CBF (true) + 0.40, but CBF (PET) is always underestimated at flow values above 65 mL/min/100 g. Iida et a123 evaluated the regional differences of tracer arrival in cerebral tissues using Hz150 and PET. Both cerebral blood flow and permeability-surface area product of water have been determined using 150water and PET. Mapping of the brain reflecting different functional areas, such as speech, movement, sensation, etc, has been accomplished by analyzing the variations of activity distributions on the H2150 PET images. 25 Oxygen-15 water also has been used for measuring myocardial blood flow by PET. 26 Usually 50 to 100 mCi is administered intravenously. To correct for blood-pool background activity, a 150-CO image is obtained and then subtracted from the 150-HzO image of the heart. Bergmann et a126measured the first-pass extraction efficiency to be nearly 96% at blood flow values of 80 to 100 mL/min/100g, and the blood flows correlated well with those from the microsphere technique. Coronary stenoses could be easily detected in dogs at rest and during dipyridamole-induced stress by the H2~50 PET technique. 27 Similar results were obtained in humans by the H2150 PET method, indicating lowest perfusion in regions of decreased myocardial uptake distal to stenosis. 28 Over the flow range of 40 to 150 mL/min/100 g in dogs, good agreement was obtained between blood flows measured by the H2150 PET and microsphere techniques, z9 Iida et al 2~measured absolute myocardial blood flow in humans using Hz150 and PET. The values were 95 --- 9 mL/min/100 g in normal humans, but they were reduced in patients with triple-vessel disease.

SAHA, MACINTYRE, AND GO

Copper-62PTSM. Copper-62 pyruvaldehydebis-N4-methyl-thiosemicarbazone (PTSM) has been evaluated for the measurement of myocardial and cerebral perfusion by PET imaging. 3~ Copper-62 has a T1/z of 9.8 minutes and it is obtained from the 62Zn/62Cu generator by eluting with 2N HCI. Copper-62 PTSM is prepared by mixing a [62Cu] acetate solution with H2 (PTSM) in ethanol followed by separation on a C18 Sep-Pak column. 3~ Biodistribution studies show rapid blood clearance, high heart-to-blood ratios, and prolonged tissue retention. The 62Cu PTSM PET technique in humans offers excellent perfusion images of the brain and heart. 3~ PET Radiopharmaceuticals for Metabolic Imaging Fluorine-18-fluorodeoxyglucose. Although the heart derives its energy primarily from nonesterified fatty acid, glucose becomes the primary source of energy at low plasma level of fatty acid. At present, 18F fluorodeoxyglucose (FDG) has become the agent of choice for metabolic imaging of the heart. Fluorine-18 has a T1/2 of 110 minutes and decays by 13+ emission. It is produced primarily in the cyclotron by 180 (p,n) 18F using H2180 as the target. 31 The 18F fluoride ion is separated by the anion-exchange method in which the fluoride ion is extracted from the column by using an immobilized potassium ion/cryptand complex. The fluoride ion is allowed to react with 1,3,4,6-tetra-O-acetyl-2-O-trifluormethane-sulfonyl-13-D-mannopyranose to yield 2-fluoro-2deoxy-D-glucose.32 The yield is nearly 50%. There are other methods of producing [18F] FDG reviewed by Kilbourn, 33 but they are not widely used. Fluorine-18 FDG has been widely used in the metabolic studies of the brain and the heart. After intravenous administration, FDG is phospholyrated to FDG-6-phosphate mediated by hexokinase. Because FDG-6-phosphate is not a substrate for glycolysis and does not undergo further metabolism, it remains trapped in the cell over the course of several hours. 34 After intravenous administration, the blood clearance has three components having Tl/2S of 0.2 to 0.3 minutes, 11.6 ___ 1.1 minutes, and 88 - 4 minutes. In estimating the absorbed doses to

CYCLOTRONS AND PET RADIOPHARMACEUTICALS

different organs from the intravenous administration of [~8F]FDG, Mejia et a135measured the organ uptakes of the tracer in humans. The uptake values were in brain, 6.9% of the administered activity; heart, 3.3%; kidney, 1.3%; liver, 4.4%; lungs, 0.9%; and bladder, 6.3%. The urinary excretion was 10.6% __. 10.9% at 1 hour postinjection a n d 21.2% _ 5.0% at 2 hours postinjection. Tumor, epileptic loci, and other metabolic disorders have been detected in brain imaging by using [lSF]FDG and PET. Di Chiro at el 36,37 first used [18F]FDG and PET to show a clear correlation between the tumor FDG uptake and the degree of malignancy in gliomas. Patronas et aP 8 showed that [18F]FDG uptake in astrocytomas can be a prognostic indicator of clinical outcome. Increased glycolysis in the tumor indicates the increased uptake of the tracer. In epilepsy patients, [18F]FDG PET imaging shows hypometabolism (decreased FDG uptake) in the region of a temporal seizure focus.38-42 Compared with other modalities such as roentgenogram, computed tomography (CT), magnetic resonance imaging (MRI), and scalp electroencephalogram, 18F [FDG] PET provides more accurate localization of seizure foci, particularly in children, as identified by neuropathology and intraoperative corticography.43 A n o t h e r important application of the [18F]FDG PET technique is in differentiating recurrent tumors from radiation necrosis secondary to therapy.44,45 These two conditions are indistinguishable on CT, MRI, and angiographic images, but they can be distinguished by the noninvasive [18F]FDG PET technique, which indicates increased uptake by the tumor versus decreased uptake in radiation necrosis. The major application of [18F]FDG PET has been in the prediction of viability of ischemic myocardium during selection of patients for coronary artery bypass surgery or angioptasty. 34,46"49 After intravenous administration, myocardial uptake of FDG after glucose load is about 1% to 4%. 34 Normal myocardium shows uniform and homogeneous [lSF]FDG uptake, and infarcted myocardium (scar) does not accumulate any activity. The reversible ischemic regions of myocardium show increased uptake. In fasting human subjects, [lSF]FDG uptake in

155

myocardium is nonuniform, but it becomes homogeneous after glucose loading. 5~ Fluorine-18 FDG images after glucose loading are of better quality than those after fasting.51 In a recent report by Go et al, 52 30% of patients diagnosed with irreversible myocardial defects by 82Rb perfusion imaging showed increased FDG uptake in myocardium, indicating myocardial viability. A recent review by Schwaiger and Hicks53provides details of metabolic imaging in humans by the use of [18F]FDG and PET. Carbon-11-palmitate. Carbon-ll has a Tl/2 of 20.4 minutes and decays by positron emission giving 511-keV photons. It is produced by the t4N(p, c~)11C reaction onnitrogen gas target in which HCO2 is formed. Carbon-ll-palmitic acid is synthesized by the Grignard reaction using pentadecyl magnesium bromide and 11CO2.54 Palmitic acid comprises approximately 25% to 30% of the circulating fatty acid in the blood and serves as one of the primary sources for energy production by the heart. Carbon-ll palmitate has been mostly used for the study of the cardiac fatty acid metabolism. After intravenous administration, it circulates bound to albumin. Myocardial uptake is characterized by initial diffusion into the myocyte where fatty acid is transferred from albumin to intracellular proteins. The fatty acid either may back-diffuse to the vascular compartment or it is thioesterifled intraceUularly. The thioesters of fatty acids undergo 13 oxidation in the mitochondria or become incorporated into triglycerides or phospholipids. 55The washout of 11C activity from the myocardium is biphasic. The early phase corresponds to the [3 oxidation of UC-palmitate, and the second slow component indicates the incorporation of fatty acid into the lipid pool as triglycerides or phospholipids. 56,57 Fatty acid uptake in ischemic myocardium is reduced due to relatively poor extraction of the tracer. 58The clearance rate in ischemic myocardium is also reduced as a result of decreased fatty acid oxidation. 59 Normal myocardial imaging with [UC]palmitare PET demonstrates homogeneous accumulation of the tracer. Ischemic myocardium is demonstrated by reduced uptake in the respective region. Infarct size measured by [UC]palmitare PET correlates well with the biochemical

156

estimate made by plasma creatine kinase. 6~ Carbon-ll palmitate has been used to assess the efficacy of thrombolytic intervention in CAD patients. 62,63Diminished uptake of the tracer in ischemic myocardium was ameliorated by thrombolysis with streptokinase 62and tissue plasminogen activator 63 soon after the onset of ischemia. Carbon-11-acetate. Carbon-ll acetate has been synthesized and evaluated for oxidative metabolic imaging of myocardium. 64-66It is synthesized by the reaction between HC-CO2 and methylmagnesium bromide, and the yield is over 99%. 64 After intravenous administration, the blood clearance is monoexponential in humans at rest. In myocardium, acetate is initially converted to acetyl-CoA by a synthase and then oxidized to x~C-CO2 in the mitochondria. Myocardial uptake and clearance are homogeneous in normal subjects. 65In infarcted myocardium, a decreased uptake and clearance of [~lC]acetate was noted, indicating reduced myocardial oxygen consumption. 66 Nitrogen-13 glutamate. Radiolabeled amino acids have been used to assess the turnover of proteins in myocardium. Nitrogen-13-glutamate is the most widely used amino acid to image human myocardium. The first-pass myocardial extraction after intravenous administration is of the order of 40% to 60%, and about 7% to 23% is metabolized. 67Myocardial uptake of [13N]glutamate is not uniform in ischemic myocardium, and the clearance of the tracer also is faster than in normal patients. 68 Zimmerman et a169 found a good correlation between [13N]glutamate uptake in the poststenotic regions and 2~ uptake in infarcted areas. In a report by Krivokapich et al, 7~[13N]glutamate was found to parallel the uptake pattern of ]3NH3 but not [lSF]FDG, indicating that it behaves as a perfusion tracer rather than a metabolic marker of ischemia.

PE T Radiopharmaceuticalsfor ReceptorImaging Various receptor-binding radiopharmaceuticals labeled with 18F and 11C have been used primarily for brain imaging and, to a lesser extent, heart imaging. In 1983, ~lC-labeled N-methylspiperone ([11C]NMSP), which binds to D2 dopamine receptors, was first used to image the neuroreceptor distribution in the brain. 71,72Carbon-ll NMSP is synthesized by N-alkylation of

SAHA, MACINTYRE, AND GO

spiperone with [~lC]methyliodide, which is produced from the precursor HCO2.71After intravenous administration, the uptake of [11C]NMSP was highest in the basal ganglia as seen on the PET images. 71 Fluorine-18-NMSP has been synthesized by nucleophilic substitution on cyclopropyl p-nitrophenyl ketone using ~SF ion. 73After intravenous administration, the radioactivity cleared from the plasma rapidly. Highest uptake was seen in caudate-putamen brain regions, and least uptake was seen in frontal cortex regions in humans, indicating the least density of receptors in the latter zones. 74 Maziere et a175 made quantitative imaging of dopamine receptors in the human brain using PET and bromine-76 bromospiperone. Other PET radiopharmaceuticals for dopamine receptor imaging include llC-SCH 23390, llC-raclopride, 76 and uC[YM-09151-2], 77,78 the latter of which showed higher affinity for D2 receptors than spiroperidol. Fluorine-18-1abeled fluoro-L-DOPA has been synthesized by nucleophilic substitution of nitro groups of two substrates, 3,4-dimethoxy-2-nitrobenzaldehyde and 6-nitropiperonal with fluoride ion (18F).79 It has been used in the imaging of the dopamine receptors in the brain in rhesus monkeys by PET, and it was found to accumulate predominantly in the basal ganglia, s~ Fluorine-18-L-DOPA has also been used in the assessment of presynaptic nigrostriatal function in Parkinson's disease. 8a Based on the suggestion that opioid peptides play an important role in human epilepsy, the highly mu-selective opiate agonist, [llC]carfentanil, has been used to localize and quantify mu opiate receptors in normal subjects and those with temporal lobe epilepsy. 82This study demonstrates a significantly increased mu opiate receptor binding in the temporal neocortex ipsilateral to the seizure focus, and reduced uptake in the mesial temporal cortex from which a seizure originates. A high-affinity opiate agonist, [11C]diprenorphine, has been used to image and quantify opiate receptors binding in humans using PET. 83This study shows much higher binding of [11C]diprenorphine for cerebral cortex and basal ganglia than to [~lC]carfentanil, indicating non-mu opiate receptor binding of the former. Another study of 10 patients with idiopathic

CYCLOTRONS AND PET RADIOPHARMACEUTICALS

epilepsy using uC-Ro15-1788 and PET showed a 29% reduction in benzodiazepine receptor in epileptic focus.84 Only a little work has been made on the PET imaging of cardiac receptors. The heart responds to changes in blood pressure and stress through the cardiac receptors, which are of two types: cholinergic and adrenergic. The former include nicotinic and muscarinic receptors, whereas the latter include the oLand 13 categories. Carbon-11-3-quinuclidinyl-4-iodobenzylate (QNB) methyliodide was used to image the baboon heart, and it gave high contrast scintigraphs. 85 However, this agent did not show any differences in cardiac receptor density in patients with dilated and hypertrophic cardiomyopathies. 86 A 13 adrenergic blocking agent, [UC]practolol, demonstrated myocardial uptake, which declined with intravenous administration of propranolol. 87 A new agent, [UC]meta-hydroxyephendrine has been developed for imaging the sympathetic nerves of the heart. 88 It has been synthesized by direct methylation of metaraminol with [llC]methyliodide and purified by high-pressure liquid chromatography, giving yield of 40% to 50%. High myocardial uptake is seen after intravenous administration, but pretreatment with a neuronal blocking drug, desioramine, inhibits the myocardial uptake of [UC]meta-hydroxyephedrine. A similar radiopharmaceutical, 6[18 F]fluorometaraminol, has also been used for neuronal mapping of the heart and gave similar results. 89 Kiesewelter et al synthesized 16et-18F-fluoro1713-estradiol by simple displacement reactions using reactive trifluoromethane sulfonate (triflate) precursors and [18F]fluoride ion.9~In bidistribution studies in female rats, this compound exhibits high affinity for estrogen receptors and has been used for the detection of breast cancer. 91

PET Radiopharmaceuticals for Tumor Studies Strauss and Conti92 used 18F FDG for the differentiation between recurring tumors and necrosis in patients with colorectal tumors, and they observed increased uptake in tumors versus decreased uptake in scars. This group also evaluated colorectal tumors before and after

157

radiation therapy using [18F]FDG PET. All colorectal recurrences were visible on the PET images, whereas a significant decrease in FDG uptake was noted after treatment. Fluorine-18 FDG has also been used to monitor growth and regression of colonic metastases to liver in patients following therapy. 93,94 Because 5-fluorouracil (FU) has been used for the therapeutic treatment of various tumors, [18F]FU has been used in the detection of these tumors with limited success. 92,95Increased accumulation in malignant tumors is seen with the use of [18F] FU PET. In a group of 10 patients with histologically proven tumors of oropharynx or hypopharynx, PET studies were performed using 18F FDG before and after chemotherapy with cisplatinum and 5-FU that demonstrated increased uptake in tumors and lymph nodes. 92 A similar study was performed in another group of 27 patients with hypopharynx, and a good correlation was obtained between FDG uptake and proliferation rate in tumor. 92 Lung tumors (bronchogenic carcinoma) have been assessed by [18F]FDG PET imaging in humans.92,96 No correlation was observed between FDG uptake and tumor histology. Fluorine-18 FDG was also found useful in the assessment of therapeutic treatment of lung tumors. 92 Fluorine-18 FDG has been used in the detection of Hodgkin's and non-Hodgkin's lymphoma. 97-99Increased uptake of FDG was seen in patients with intermediate grade or highgrade but not low-grade lymphoma.97 Also, response to therapy in lymphoma patients could be monitored by [lSF] FDG and PET. 99 Both primary and metastatic breast cancer have been successfully detected by the use of [18F]FDG and PET in patients before and following combination chemohormonotherapy.10~ Lymph node involvement was also seen in some cases. 1~ Melanoma has been detected by [18F]FDG and alC-labeled alpha-aminoisobutyric acid (AIB) using PET. 1~176 FDG serves as a metabolic indicator, and AIB is incapable of crossing the blood-brain barrier (BBB). Both primary and metastatic lesions accumulate both tracers in varying degrees. Bone and soft tissue tumors in patients have

158

SAHA, MACINTYRE, AND GO

been detected by PET using [18F]FDG and [13N]glutamate.1~176 In a small group of patients with musculoskeletal tumors, good correlation was obtained between [18F]FDG uptake, indicating glucose utilization rate and tumor grade. 1~ sarcoma treated with chemotherapy showed increased uptake of [13N]glutamate in areas of viable tumor cells and decreased uptake in areas of necrotic tumor. 1~ Carbon-ll-labeled AIB has been used in patients with malignant fibrous histiocytoma, indicating high target-to-background ratios in extremity lesions. 108 Yamamoto et al 1~ and Hawkins et a111~ showed that 68Ga-labeled ethylenediaminetetraacetic acid (EDTA) can be used in conjunc-

tion with PET in the detection of brain tumors. GalIium-68-EDTA is excluded from the brain by an intact BBB, but it accumulates in the lesions where the BBB is altered or broken. Fuziwara et a1111employed 11C-labeled methionine in the detection of lung cancer and found a good correlation between uptake of [llC]methionine and tumor histology. Mineura et a1112 recently used [llC]L-methionine and PET in the detection of gliomatosis cerebri and found a good anatomic correlation between the extent of tumor cells and high tracer uptake. ACKNOWLEDGMENT The authors wish to thank Sandra Petraus and Rita Buzzelli for their excellent typing of the manuscript.

REFERENCES 1. Friedlander G, Kennedy JW, Miller JM: Nuclear and Radiochemistry (ed 3). New York, NY, Wiley, 1981 2. Harvey BG: Introduction to nuclear physics and chemistry. Englewood Cliffs, NJ, Prentice-Hall, 1962, p 272 3. Krizek H, Lembares N, Dinwoodie R, et al: Production of radiochemically pure 13NH3 for biomedical studies using the 160 (p,et) 13N reaction. J Nucl Med 14:629-630, 1973 4. Tilbury RS, Dahl JR, Monahan WB, et al: The production of 13N-labeled ammonia for medical use. Radiochem Radioanal Lett 8:317-323, 1971 5. Phelps ME, Hoffman EJ, Coleman RE, et al: Tomographic images of blood pool and perfusion in brain and heart. J Nucl Med 17:603-612, 1976 6. Schelbert HR, Phelps ME, Hoffman EJ, et al: Regional myocardial perfusion assessed with ammonia and positron emission computerized axial tomography. Am J Cardio143:209-218, 1979 7. Schelbert HR, Phelps ME, Huang SC, et al: N-13 ammonia as an indicator of myocardial blood flow. Circulation 63:1259-1272, 1981 8. Bergmann SR, Hack S, Tewson T, et al: The dependence of accumulation of ~3NH3 by myocardium on metabolic factors and its implication for quantitative assessment of perfusion. Circulation 61:34-43, 1980 9. Tamaki N, Yonekura Y, Senda M e t ai: Myocardial positron computed tomography with N-13 ammonia at rest and during exercise. Eur J Nucl Med 11:246-251, 1985 10. Tamaki N, Yonekura Y, Senda et al: Valve and limitation of stress thaUium-201 single photon emission computed tomography: Comparison with nitrogen-13 ammonia positron tomography. J Nucl Med 29:1181-1188, 1988 11. Goldstein RA, Kirkeeide RL, Smalling RW, el al: Changes in myocardial perfusion reserve after PTCA: Noninvasive assessment with positron tomography. J Nucl Med 28:1262-1267, 1987 12. Yano Y, Chu P, Budinger TF, et al: S2Rb generators for imaging studies. J Nucl Med 18:46-50, 1977 13. Saha GB, Go RT, Maclntyre WJ, et al: Use of

82Sr/82Rb generator in clinical PET studies. Nucl Med Bioi 17:763-768, 1990 14. Strauss HW, Pitt B: Evaluation of cardiac function and structure with radioactive tracer techniques. Circulation 57:645-654, 1978 15. Gould KL, Goldstein RA, Muilani NA, et al: Noninvasive assessment of coronary stenosis by myocardial perfusion imaging during pharmacologic coronary vasodilation. VIII. Clinical feasibility of positron cardiac imaging without a cyclotron using generator-produced rubidium-82. J Am Coil Cardiol 7:775-789, 1981 16. Go RT, Marwick TH, Maclntyre W J, et al: A prospective comparison of rubidium-82 PET and thallium-201 SPECT myocardial perfusion imaging utilizing a single dipyridamole stress in the diagnosis of coronary artery disease. J Nucl Med 31:1899-1905, 1990 17. Goldstein RA, Muilani NA, Maranai SK, et ai: Myocardial perfusion with rubidium-82. 1L Effects of metabolic and pharamcologic intervention. J Nucl Med 24:907925, 1983 18. Wilson RA, Shea M, De Landsure C, et al: Rb-82 myocardial uptake and extraction after transient ischemia: PET characteristics. J Comp Assist Tomogr 11:60-66, 1987 19. Welch M J, Lifton JF, Ter-Pogossian MM: The preparation of millieurie quantities of oxygen-15 labeled water. J Label Comp 5:168, 1969 20. Iida H, Kanno I, Takahashi A, et al: Measurement of absolute myocardial blood flow with H2150 and dynamic positron emission tomography. Circulation 78:105-115, 1988 21. Herscovitch P, Markham J, Raichle ME, et al: Brain blood flow measured with intravenous O-15 H20. I. Theory and error analysis. J Nucl Med 24:782-789, 1983 22. Raichle ME, Martin WRW, Herscovitch P, et al: Blood flow measured with intravenous O-15 H20. ]1. Implementation and validation. J Nucl Med 24:790-789, 1983 23. Iida H, Higano S, Tomura N, et ai: Evaluation of regional differences of tracer appearance time in cerebral tissues using [1SO]water and dynamic positron emission tomography. J Cereb Blood Flow Metab 8:285-288, 1988

CYCLOTRONS AND PET RADIOPHARMACEUTICALS

24. Herscovitch P, Raichle ME, Kilbourn MR, et al: Positron emission tomographic measurement of cerebral blood flow and permability-surface area product of water using 1SO-water and 11C-butanol. J Cereb Blood Flow Metab 7:527-542, 1987 25. Fox PT, Mintun MA: Noninvasive functional brain mapping by change-distribution analysis of averaged PET images of H2150 tissue activity. J Nucl Med 30:141-149, 1989 26. Bergmann SR, Fox KA, Rand AL, et al: Quantification of regional myocardial blood flow in vivo with H2150. Circulation 70:724-733, 1984 27. Knable RM, Fox KA, Sobel BE, et al: Characterization of the functional significance of subcritical coronary stenoses with H2150 and positron emission tomography. Circulation 71:1271-1278, 1985 28. Walsh MN, Bergmann SR, Steele RL, et al: Delineation of impaired regional myocardial perfusion by positron emission tomography with H2150. Circulation 78:612-620, 1988 29. Huang SC, Schwaiger M, Carson RE, et al: Quantitative measurement of myocardial blood flow with oxygen-15 water and positron emission tomography: An assessment of potential and problems. J Nucl Med 26:616-625, 1985 30. Green MA, Mathias CJ, Welch M J, et al: Cooper-62labeled pyruvaldehyde bis (N4-methylthio-semicarbazonato) copper (II): Synthesis and evaluation as a positron emission tomography tracer for cerebral and myocardial perfusion. J Nucl Med 31:1989-1996, 1990 31. Kilbourn MR, Hood JT, Welch MJ: A simple 180 water target for 18F production. Int J Appl Radiat Isot 27:559-602, 1984 32. Hamacher K, Coenen HH, Stocklin G: Efficient sterospecific synthesis of no-carrier-added 2-18F-fluoro-2 deoxy-D-glucose using aminopolyether-supported nucleophilic substitution. J Nucl Med 27:235-284, 1986 33. Kilbourn MR: Fluorine-18 labeling of radiopharmaceuticals. NAS-No3203, Washington, DC, National Academy Press, 1990 34. Phelps ME, Hoffman E J, Selin C, et al: Investigation of F-18-fluoro-2-deoxy-glucose for the measure of myocardial glucose metabolism. J Nucl Med 19:1311-1319, 1978 35. Mejia AA, Nakamura T, Masatoshi I, et al: Estimation of absorbed doses in humans due to intravenous administration of fluorine-18-fluorodeoxyglucose in PET studies. J Nucl Med 32:699-706, 1991 36. Di Chiro G, DeLa Paz RL, Brooks RA, et al: Glucose utilization of cerebral gliomas measured by [18F] fluorodeoxyglucose and positron emission tomography. Neurology 32:1223-1239, 1982 37. Di Chiro G: Positron emission tomography using [18F] fluorodeoxyglucose in brain tumors. Invest Radiol 22:360-371, 1987 38. Patronas NH, Di Chiro G, Kufta C, et al: Prediction of survival in glioma patients by means of positron emission tomography. J Neurosurg 62:816-822, 1985 39. Kuhl DE, Engel J Jr, Phelps ME, et al: Epileptic patterns of local cerebral metabolism and perfusion in humans determined by emission computed tomography of 18F-FDG and 13NH3. Ann Neurol 8:348-360, 1980 40. Theodore WH, Newmark ME, Sato S, et al: F-18-

159

fluorodeoxyglucose positron emission tomography in refractory complex partial seizures. Ann Neurol 14:429-437, 1983 41. Abou-Khalil BW, Siegel GJ, Sackellares JC, et al: Positron emission tomography studies of cerebral glucose metabolism in chronic partial epilepsy. Ann Neurol 22:480486, 1987 42. Engel J Jr, Henry TR, Rising MW, et al: Presurgical evaluation for partial epilepsy: Relative contributions of chronic depth-electrode recording versus FDG-PET and scalp-sphenoidal ictal EEG. Neurology 40:1670-1677, 1990 43. Fisher RS, Frost JJ. Epilepsy. J Nucl Med 32:651-659, 1991 44. Di Chiro G, Oldfield E, Wright DC, et al: Cerebral necrosis after radiotherapy and for intraarterial chemotherapy for brain tumors: PET and neuropathologic studies. AJNR 8:1083-1091, 1987 45. Doyle WK, Budinger TF, Valk PE, et al: Differentiation of cerebral radiation necrosis from tumor recurrence by XSF-FDG and 82Rb positron emission tomography. J Comp Assist Tomogr 11:563-570, 1987 46. Ratib O, Phelps ME, Huang SC, et al: Positron tomography with deoxyglucose for estimating local myocardial glucose metabolism. J Nucl Med 23:577-586, 1982 47. Marshall RC, Tillisch JH, Phelps ME, et al: Identification and differentiation of resting myocardial ischemia and infarction in man with positron computed tomography, 18F-labeled fluorodeoxyglucose and N-13 ammonia. Circulation 67:766-778, 1983 48. Schwaiger M, Brunken R, Grover-McKay M, et al: Regional myocardial metabolism in patients with acute myocardial infarction assessed by positron emission tomography. J Am Coil Cardiol 8:800-808, 1988 49. Brunken R, Schwaiger M, Grover-McKay, et al: Positron emission tomography detects tissue metabolic activity in myocardial segment with persistent thallium perfusion defects. J Am Coil Cardiol 10:557-567, 1987 50. Gropler RJ, Siegel BA, Lee KJ, et al: Nonuniformity in myocardial accumulation of fluorine-18-fluorodeoxyglucose in normal fasted humas. J Nucl Med 31:1749-1756, 1990 51. Berry JJ, Hanson MW, Coates D, et al: FDG cardiac PET image quality is critically affected by glucose loading. J Nucl Med 31:840, 1990 (abstr) 52. Go RT, Cook SA, MacIntyre WJ, et al: Incidence of hibernating myocardium in patients with irreversible perfusion defects: Detection by perfusion and metabolic PET imaging, in Bullet N, Henderson AH, Krayenbfilh (eds): Left veutricular function in stunned and hibernating myocardium. Proceedings of a symposium held during the XIIIth Congress of the European Society of Cardiology, Amsterdam. Excerpta Medica, 1991, pp 69-76 53. Schwaiger M, Hicks R: The clinical role of metabolic imaging of the heart by positron emission tomography. J Nucl Med 32:565-578, 1991 54. Weiss ES, Hoffman EJ, Phelps ME, et al: External detection and visualization of myocardial ischemia with nC-substrates in vivo and in vitro. Circ Res 39:24-32, 1976 55. Neely JR, Morgan JE: Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Ann Rev Physio136:412-459, 1974 56. Schon HR, Schelbert HR, Robinson G, et al: C-11

160

labeled palmitic acid for the noninvasive evaluation of regional myocardial fatty acid metabolism with positron computed tomography. 1. Kinetics of llC-palmitic acid in normal myocardium. Am Heart J 103:532-547, 1981 57. Lerch RA, Ambos HD, Bergmann SR, et al: Kinetics of positron emitters in vivo characterized with a beta probe. Am J Physio1242:H62-H67, 1982 58. Bergmann SR, Fox KAA, Geltman EM, et al: Positron emission tomography of the heart. Prog Cardiovasc Dis 28:165-194, 1985 59. Schon HR, Schelbert HR, Najafi A, et al: C-11labeled palmitic acid for the noninvasive evaluation of regional myocardial fatty acid metabolism with positron computed tomography. II. Kinetics of C-11 palmitic acid in acutely ischemia myocardium. Am Heart J 1003:548-561, 1982 60. Sobel BE, Weiss ES, Welch M J, et al: Detection of remote myocardial infarction in patients with positron emission transaxial tomography and intravenous HCpalmitate. Circulation 55:853-857, 1977 61. Ter-Pogossian MM, Klein MS, Markham J, et al: Regional assessment of myocardial metabolic integrity in vivo by positron emission tomography with C-11 palmitate. Circulation 61:242-255, 1980 62. Bergmann SR, Lerch RA, Fox KAA, et al: Temporal dependence of beneficial effects of coronary thrombolysis characterized by positron tomography. Am J Med 73:573581, 1982 63. Sobel BE, Geltman EM, Tiefenbrunn AJ, et al: Improvement of regional myocardial metabolism after coronary thrombholysis induced with tissue type plasminogen activator or streptokinase. Circulation 69:983-990, 1984 64. Brown MA, Marshall DR, Sobel BE, et al: Delineation of myocardial oxygen utilization with carbon-ll-labeled acetate. Circulation 76:687-696, 1987 65. Henes CG, Bergmann SR, Walsh MN, et al: Assessment of myocardial oxidative metabolic reserve with positron emission tomography and carbon-ll acetate. J Nucl Med 30:1489-1499, 1989 66. Brown MA, Myears DW, Bergmann SR: Validity of estimates of myocardial oxidative metabolism with C-11 acetate and positron emission tomography despite altered patterns of substrate utilization. J Nucl Med 30:187-193, 1989 67. Henze E, Schelbert HR, Barrio JR, et al: Evaluation of myocardial metabolism with N-13 and C-11-1abeled amino acids and positron computed tomography. J Nucl Med 23:671-681, 1982 68. Knapp WH, Helus F, Ostertag H, et al: Uptake and turnover of L-(N-13) glutamate in the normal human heart and in patients with coronary artery disease. Eur J Nucl Med 7:211-215, 1982 69. Zimmerman R, Tillmans H, Knapp WH, et ai: Regional myocardial mitrogen-13 glutamate uptake in patients with coronary artery disease: Inverse post-stress relation to thallium-201 uptake in ischemia. J Am CoIl Cardiol 11:549-556, 1988 70. Krivokapich J, Barrio JR, Huang SC, et al: Dynamic positron tomographic imaging with nitrogen-13 glutamate in patients with coronary artery disease: Comparison with

SAHA, MACINTYRE, AND GO

nitrogen-13 ammonia and fluorine-18 fluorodeoxyglucose imaging. J Am Coil Cardio116:1158-1167, 1990 71. Wagner HN Jr, Burns HD, Dannals RF, et al: Imaging dopamine receptors in the human brain by positron emission tomography. Science 221:1264-1266, 1983 72. Wong DF, Wagner HN, Jr, Dannals RF, et al: Effects of age on dopamine and serotonin receptor measured by positron tomography in the living human brain. Science 226:1391-1396, 1984 73. Shiue CY, Fowler JS, Wolf AP, et al: No-carrier added fluorine-18-1abeled N-methylspiroperidol: Synthesis and biodistribution in mice. J Nucl Med 27:226-234, 1986 74. Arnett CD, Wolf AP, Shiue CY, et al: Improved delineation of human dopamine receptors using [lSF]-Nmethylspiroperiodol and PET. J Nucl Med 27:1878-1882, 1986 75. Maziere B, Loch C, Baron JC, et al: In vivo quantitative imaging of dopamine receptors in human brain using positron emission tomography and [76Br] bromo-spiperone. Eur J Pharmacol 114:267-272, 1985 76. Farde L, Halidin C, Stone-Elander S, et al: PET analysis of human dopamine receptor subtypes using HCSCH 23390 and IlC-raclopride. Psychopharmacology (Berl) 92:278-824, 1987 77. Hatano K, Ishiwata K, Kawashima K, et al: Dzdopamine receptor specific brain uptake of cardon-ll labeled YM-09151-2. J Nucl Med 30:515-522, 1989 78. Hatazawa J, Hatano K, Ishiwate K, et al: Measurement of D2 dopamine receptor specific carbon-ll-YM09151-2 binding in the canine brain by PET: Importance of partial volume correction. J Nucl Med 32:713-718, 1991 79. Lemaire C, Guillaume M, Cantineau R, et al: Nocarrier-added regioselective preparation of 6-[18F]fluor-o-L Dopa. J Nud Med 31:1247-1251, 1990 80. Doudit D, Cohen RM, Finn R, et al: 6-F-18-L-DOPA brain imaging in asymptomatic MPTP-lesioned monkeys. J Nucl Med 29:820, 1988 (abstr) 81. Martin WRW, Palmer MR: Assessment of presynaptic nigrostriatal function in Parkinson's disease. J Nucl Med 30:761, 1989 (abstr) 82. Frost JJ, Mayberg HS, Fisher RS, et al: Mu-opiate receptors measured by positron emission tomography in temporal lobe epilepsy. Ann Neuro123:231-237, 1988 83. Frost J J, Maybert HS, Sadzot B, et al: Comparison of 11C-diprenorphine and llC-carfentanil binding to opiate receptors in humans by positron emission tomography. J Cereb Blood Flow Metab 10:484-492, 1990 84. Savic I, Roxand P, Sedvall G, et al: In vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci. Lancet 2:863-866, 1988 85. Maziere M, Comar D, Godot JM, et al: In vivo characterization of myocardium muscarinic receptors by positron emission tomography. Life Sci 29:2391, 1981 86. Syrota A, Maziere A, Crouzel M, et al: Visualization of muscarine acetylcholine receptors in the human heart using llC-methyl-QNB and positron emission tomography, in Raynaud C (ed): Nuclear Medicine and Biology. Paris, France, Pergammon, 1982, pp 2503-2520 87. Syrota A, Dormont D, Berger J, et al: C-11 ligand binding to adrenergie and muscarinic receptors of the

CYCLOTRONS AND PET RADIOPHARMACEUTICALS

human heart studied in vivo by PET. J Nucl Med 24:20, 1983 (abstr) 88. Rosenspire KC, Haka MS, Van Dort ME, et ai: Synthesis and preliminary evaluation of carbon-ll-metahydroxyephedrine: A false transmitter agent for heart neuronal imaging. J Nucl Med 31:1328-1334, 1990 89. Wieland DM, Rosenspire KC, Hutchins GD, et al: Neuronal mapping of the heart with 6-[18F]fluoro-metarami nol. J Med Chem 33:956-964, 1990 90. Kiesewetter DO, Kilbourn MR, Landvatter SW, et al: Preparation of four fluorine-18 labeled estrogens and their selective uptakes in target tissues of immature rats. J Nucl Med 25:1212-1221, 1984 91. Mintun MA, Welch MJ, Siegel BA, et ai: Breast cancer: PET imaging of estrogen receptors. Radiology 169:45-48, 1988 92. Strauss LG, Conti PS: The applications of PET in clinical oncology. J Nucl Med 32:623-648, 1991 93. Yonekura Y, Benua RS, Brill AB, et al: Increased accumulation of 2-deoxy-2-[F-18]fluor-D-glucose in liver metastases from colon carcinoma. J Nucl Med 23:11311137, 1982 94. Kim EE, Chung SK, Tilbury R, et al: Differentiation of residual or recurrent tumors from post-treatment changes with PET using F-18-FDG. J Nucl Med 31:803, 1990 (abstr) 95. Abe Y, Fukuda H, Ishiwata K, et al: Studies on 18F-labeled pyrimidines. Tumor uptakes of 18F-5-fluorouracil, lSF-5-fluorouridine, and ~SF-fluorodeoxyuridine in animals. Eur J Nucl Med 8:258-261, 1983 96. Knopp MV, Strauss LG, Haberkorn U, et al: Use of positron emission tomography for optimized therapy management of patients with lung tumors. Eur J Nucl Med 16:560, 1990 97. Leskinen-Kallio S, Ruotsalainen U, Ter~is M, et al: The uptake of [llC]methionine and FDG in non-Hodgkins lymphorna. European Workshop on FDG in Oncology, Heidelburg, Germany, June 15-16, 1990 98. Ikada J, Yoshikawa K, Imazeki K, et al: The use of FDG-PET in the detection and management of malignant lymphoma: Correlation of uptake with prognosis. J Nucl Med 32:686-691, 1991 99. Yoshikawa K, Okada J, Uno K, et al: Evaluation of therapeutic effect on the malignant lymphoma by dynamic positron emission tomographic technique using fluorine-18 2-deoxy-2-fluor-D~glucose~ J Nucl Med 30:910, 1987 (abstr) 100. Wahl RL, Cody R, Hutching G, et al: Sequential quantitative FDG/PET assessment of the metastatic re-

161

sponse of breast carcinomas to chemohormonotherapy. J Nucl Med 31:746, 1990 (abstr) 101. Wahl RL, Cody R, August D: Initial evaluation of FDG PET for the staging of the axilla in newly-diagnosed breast carcinoma patients. J Nucl Med 32:981, 1991 (abstr) 102. Wahl RL, Cody R, Hutchins G, et al: Primary and metastatic breast carcinoma: Initial clinical evaluation with PET with the radiolabeled glucose analogue 2-[lSF-]-fluorodeoxy-2-D-glucose. Radiology 179:765-770, 1991 103. Hoh CK, Maddahi J, Glaspy J, et al: PET total body imaging of breast cancer with FDG and F-18 ion. J Nucl Med 32:981, 1991 (abstr) 104. Strauss LG, Tilgen W, Dimitrakopoulou A, et al: PET studies with F-18-deoxy-glucose (FDG) in patients with metastatic melanoma prior to and after therapy. J Nucl Med 31:804, 1990 (abstr) 105. Conti PS, Sordillo PP, Schmall B, et al: Tumor imaging with C- 1I-labeled alpha-aminoisobutyric acid (AIB) in a patient with advanced malignant melanoma. Eur J Nucl Med 12:352-356, 1986 106. Kern KA, Brnnetti A, Norton JA, et al: Metabolic imaging of human extremity musculoskeleta! tumors by PET. J Nud Med 29:181-186, 1988 107. Reiman RE, Rosen G, Gelbard AS, et al: Imaging of primary Ewing sarcoma with N-13-L-glutamate. Radiology 142:495-500, 1982 108. Schmall B, Conti PS, Bigler RE, et al: Imaging studies of patients with malignant fibrous histiocytoma using C-11-aipha aminoisobutyric acid (AIB). Clin Nucl Med 1:22-26, 1987 109. Yamamoto YL, Thompson CJ, Meyer E, et al: Dynamic positron emission tomography for study of cerebral hemodynamics in cross section of the head using positron emitting 6SGa-EDTA and 77Kr. J Comput Assist Tomogr 1:43-56, 1977 110. Hawkins RA, Phelps ME, Huang SC, et al: A kinetic evaluation of blood-brain-barrier permeability in human brain tumors with [68Ga]EDTA and positron emission tomography. J Cereb Blood Flow Metab 4:507-515, 1984 11 I. Fuziwara T, Matsuzawa T, Kubota K, et al: Relationship between histologic type of primary lung cancer and carbon-ll-L-methionine uptake with postiron emission tomography. J Nncl Med 30:33-37, 1989 112. Mineura K, Sasajima T, Kowada M, et al: Innovative approach in the diagnosis of gliomatosis cerebri using carbon-ll-L-methionine positron emission tomography. J Nucl Med 32:726-728, 1991