current and future radiopharmaceuticals for brain imaging with single photon emission computed...

Current and Future Radiopharmaceuticals for Brain Imaging With Single Photon Emission Computed Tomography

Hank F. Kung, Yoshiro Ohmomo, and Mei-Ping Kung

Development of radiopharmaceuticals for functional brain imaging has progressed rapidly in recent years. Measurement of regional cerebral blood flow in humans can be achieved by using [1231]-iodoamphetamine or [ssmTC]-HMPAO. Several other lipid-soluble [sSmTc]-technetium complexes are currently undergo- ing clinical trials. New lz31-1abeled agents designed to measure central nervous system receptors, including

D1 and D2 dopamine, serotonin, muscarinic, and benzodiazepine receptors, have been developed. In conjunction with single photon emission computed tomography, they may provide useful tools to evaluate brain function related to changes in receptor concentration. �9 1990 by W.B. Saunders Company.

T RADITIONAL brain imaging agents, which have been used in nuclear medicine for the

past 40 years, have been essential in the detection of the breakdown of the blood-brain barrier. The radiopharmaceuticals used in this type of procedure customarily are agents that can detect the breakdown of the barrier and therefore show a positive uptake in the region. These types of studies are generally effective in localizing focal diseases such as neoplasma, abscesses, and infarc- tions. However, over the past 10 or 15 years, other modalities in radiology have developed, such as radiography, computed tomography, and, more recently, nuclear magnetic resonance imaging, which are more effective in detecting these types of anatomical defects. Therefore, nuclear medicine procedures have to compete with these newer types of imaging modalities instead of looking at the morphology of the brain; the detection of brain function based on tracer princi- ples will be the major application in the future. The traditional brain imaging agents using technetium-labeled pertechnetate have not been used in nuclear medicine for the past few years. However, radiopharmaceuticals that have been recently developed for functional imaging, such

From the Department of Radiology, University of Pennsyl- vania, Philadelphia, PA; Division of Radiopharmaceutical Chemistry, Osaka University of Pharmaceutical Sciences, Osaka, Japan; and the Department of Psychiatry, University of Pennsylvania, PA.

Supported by National Institutes of Health Grants No. NS-15809 and NS-24538, and a grant from Nihon Medi- Physics, Tokyo, Japan.

Address reprint requests to Hank F. Kung, PhD, Depart- ment of Radiology, Division of Nuclear Medicine, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadel- phia, PA 19104.

�9 1990 by W.B. Saunders Company. 0001-2998/90/2004-0002505.00/0

as iodine 123 and technetium 99m regional perfusion agents, have been introduced into regu- lar clinical use. This type of brain imaging could find extended use in the brain imaging studies typically performed in nuclear medicine. ]'2

BRAIN PERFUSION IMAGING AGENTS

Measurement of regional cerebral blood flow in humans has been achieved by using xenon 133 gas. The technique is based on the Kety-Schmidt technique. 3 The noninvasive technique involves the inhalation of xenon gas while the radioactiv- ity in each specific region of the brain is moni- tored with gamma detector probes. The xenon technique is limited by the poor resolution due to the less than optimal gamma ray energy (80 keV) emitted by 133Xe. The method could also be used to accumulate data for single photon emission computed tomography (SPECT) imaging; however, due to the physical characteristic of the gamma ray and the fast washout of xenon from the normal brain tissue, the image quality of xenon blood flow with SPECT is generally very poor. 4'5

In the past 10 years, a large number of iodine-labeled monoamines and diamines have been developed. 6-16 The first iodinated amine reported in the literature for measuring regional brain perfusion was iodoantipyrine. 6 This compound is very lipid soluble and therefore is easily passed through the intact blood-brain barrier. Radioactive labeled 123I-iodoantipyrine can easily cross the cell membrane by a simple diffusion mechanism. However, this compound does not have a trapping mechanism for brain retention. Therefore, it is washed out from the brain very rapidly. The trapping mechanism is especially crucial in SPECT imaging, which requires ] 0 to 60 minutes of data acquisition time with the

290 Seminars in Nuclear Medicine, Vol XX, No 4 (October), 1990: pp 290-302

BRAIN RADIOPHARMACEUTICALS FOR SPECT 291

current single- or dual-headed gamma camera- based equipment. The current status of SPECT instrumentation places stringent requirements on the biologic properties of tracers in order for it to be useful in the measurement of regional cerebral perfusion. In addition to showing high uptake and retention in the brain, the tracer has to remain fixed (no change in regional distribution) for a period of time, preferably 30 to 60 minutes, to allow for adequate data collection. Tracer development based on 123I-labeled compounds has been concentrated on the development of a trapping mechanism for long brain retention, fixed regional distribution reflecting regional blood perfusion, and minimal in vivo metabolism.

In 1976, it was reported that carbon 11 alkyl- amines show high uptake and retention in both the lungs and the brain. 7 It was suggested that these amines are trapped in the brain by amine metabolism (either by the monoamine oxidase [MAO] or by the mixed function oxidase [MFO]) and that they may be useful as imaging agents to evaluate lung and brain metabolism. Indepen- dently, another group of amines, iodinated cata- col amine congeners (4-I-DPIA), s'l~ showing high brain uptake and prolonged retention were reported. The design of these molecules was based on their structural similarities to dopamine, mescaline, amphetamine, and other psy- chotomimetic agents. Therefore, by default, it is generally assumed that these agents, and later the iodinated amphetamines, are neurotransmit- ter analogues with receptor binding properties. In 1980, a series of selenium 75 diamines (MOSE, PIPSE) (Fig 1) was reported. 11'12 In this type of agent, the trapping mechanism was proposed to be based on pH shift between the blood and brain tissue. Later, based on the same hypothesis, an iodinated diamine, HIPDM, was developed as a brain perfusion imaging agent. 13'14 Based on a series of amphetamine analogs, an iodinated monoamine N-isopropyl-4-iodo-amphetamine (IMP) was developed. 15-1s Currently, most clinical evaluations are conducted using either IMP or H1PDM (Fig 2). IMP received final Food and Drug Administration approval in 1988. This is the agent currently being used in nuclear medicine clinics.

It is now generally accepted that the minimum criteria for brain perfusion imaging agents are (1) they can pass through the intact blood-brain

PIPSE /---X /--X

MOSE

Fig 1. Chemical structures of MOSE and PIPSE.

barrier; (2) they show high first-pass extraction; (3) they show prolonged retention in the brain; (4) they display effective regional distribution in the brain; and (5) they show little or no metabolism. The agents currently being used, based on 1231- or 99mTc-labeled compounds, have for the most part fulfilled these requirements. After an intravenous injection, iodinated IMP displays a high uptake in the brain. In addition to this brain uptake, there is significant uptake in the lungs and liver and a rapid excretion in the urine. The initial high brain uptake and also the high retention at later time points is the basis of SPECT imaging of the brain. However, due to the presence of a high level of activity in the lungs, there is a significant amount of residual activity in the blood circulation at later time points (1 hour postinjection). This residual blood level ultimately contributes to what is termed "redistribution" of these iodinated amines in the brain. The initial uptake in the brain region more or less reflects the regional perfusion. However, due to the differential washout from different regions of the brain, the SPECT images obtained at later time points may not be the same as those obtained in the initial time period. It is now generally accepted that the iodinated amines are taken up by the brain by simple diffusion. Follow- ing the initial uptake, the amines are retained in the brain, but the retention mechanism (or mechanisms) is less well defined. 19'2~ At least four different types of mechanisms could be responsible for the retention in the brain: amine metabolism, nonspecific binding sites, pH shift, and specific binding sites in the brain. All of these factors may play a role in the ultimate retention of these agents in the brain. The exact mechanism has not yet been determined, and the

292 KUNG, OHMOMO, AND KUNG

OH

C H 3 ~ N ~ N t C H 3

I

CH 3 I

CH2CHNHCH(CH3) 2

HIPDM IMP Fig 2. Chemical structures of

HIPDM and IMP.

retention mechanism in the disease state may also be changing. The pattern of distribution may also be changed because of the differences in the retention mechanism.

Iodinated compounds have provided initial success in routine regional brain perfusion studies. However, the iodinated compounds are not as convenient as the 99mTc-labeled compounds with comparable properties. In the 1970s, several neutral and lipid soluble technetium compounds that pass through the blood-brain barrier were demonstrated. 21"23 However, despite the high initial brain uptake in this type of neutral technetium complex, the retention time is not long enough for evaluation of regional brain perfusion with SPECT.

In 1984, the synthesis and biodistribution of neutral lipid-soluble 99roTe complexes that cross the blood-brain barrier were reported, 24 Three derivatives of bis-aminoethanethiol (BAT) derivatives (Fig 3) formed neutral lipid-soluble complexes with 99mTc and displayed high in vivo brain uptake. Monkey imaging of 99mTc-BAT- tetramethyl-bis-aminoethanethiol (TM) compound displayed a clear view of the brain, suggest- ing high first-pass extraction of this agent into normal brain tissue. However, the retention of these compounds in the brain was not suitable for SPECT imaging. At that time, it was generally accepted that a single-head rotating camera

would require 30 to 60 minutes for data acquisition. Therefore, most of the research efforts were to develop agents with longer retention and fixed regional distribution in the brain.

It is important to recognize that the BAT ligand system is unique in that there are four ionizable atoms attached to the ligand: two S-H and two N-H. After complexing, three of the four ionizable hydrogens are ionized leaving one N-H group intact. The center core is a plus three-charged TcVO(III). Therefore, the positive charges on technetium and negative charges from the ligand cancel each other, resulting in the formation of a neutral complex. This is the unique feature of the BAT ligand system. With- out the residual N-H group, the 99mTc-BAT complexes will not be neutral (Fig 3). Other types of substituted 99mTc-BAT complexes were reported. 25-29

The successful compound in the N2S 2 series is 99mTc-L,L-ethyl cysteinate dimer (ECD) (Fig 4). 30.32 It is a diester of a neutral 99mTc N2S 2 complex and is optically active. The L,L-isomer, fortunately, shows the desired brain uptake and prolonged retention. The D,D-isomer also displays high initial uptake, but the brain retention is disappointing. 31 The proposed brain retention mechanism for 99mTc-ECD is based on the specific hydrolysis of one of the ester groups to an acid (Fig 4); consequently, the water-soluble acid

Fig 3. Formation of SS'Tc-BAT i complexes. Arrows indicate the ion- �9 izable hydrogens.

JlP

t R l h " SH

H 4 \

t HS ,~R 1

(TcVO) § RlyS,.l~ "r k

\ I

BAT-TM R I :CH 3


C2HsOO c N COOC2H s .4\ / [99mTc]ECD

Fig 4. Chemical structure of S~"Tc-ECD.

is trapped in the brain. Apparently, the hydrolysis process is a very specific enzymatic reaction. The most interesting aspect of the enzymatic process is that it is stereo-specific and only happens in the brains of primates (monkeys and humans), but not in rats or rabbits. The specific mechanism is worth noting because the perfusion images obtained by this agent are probably a combination of perfusion and the specific enzyme reaction.

Another ligand system containing N 4 for complexing technetium has been investigated inten- sively. The initial study with cyclam suggested that the technetium-cyclam complex is a plus one-charged complex with a TcVO~ ] center core. "35 However, interest in the 99~Tc-cyclam (Fig 5) and subsequent lipid complexes de- creased dramatically because they appeared to be devoid of any heart or brain uptake. 36 Neutral lipid-soluble 99mTc complexes based on N 4 ligand systems were developed later. 37"40 The chemical modification of cyclam, changing from a cyclic N 4 system to an open N 4 system, appeared to change the 99mTC core (TcVO +3) and, ultimately, the structure of the final complex (Fig 5). The

open ring system, propylene amine oxime (PnAO), is a dioxime ligand. After complexing with TcVO(III), the ligand loses two hydrogen atoms from N-H. In addition, the complex also forms an intramolecular hydrogen bond, thus losing another hydrogen atom. The plus-three charges on the TcVO(III) are canceled by the three negative charges created by ionization of two N-H and one O-H. Despite recent progress in technetium chemistry, the formation of a neutral complex with PnAO based on the same center core as that for 99mTc-BAT complexes TcVO § is hardly a predicted or predetermined event.

HMPAO (hexamethyl propylene amine oxime) (Fig 5), an optically active ligand, was developed by modifying the neutral and stable 99mTc-PnAO.41-42 It was the first FDA-approved 99mTc brain perfusion imaging agent. The agent has reached nuclear medicine clinics for routine human use. 435~ Not only is the agent lipid- soluble and able to penetrate the intact blood- brain barrier, it also displays very high in vivo instability. It reacts in seconds after intravenous injection, probably with intracellular glutathione, and is trapped inside the brainS~'s2; thus, it fulfills the basic criteria for a useful brain perfusion imaging agent. The regional uptake and retention are generally related to the regional perfusion. Poor in vitro stability of the technetium core often makes this agent less reliable, 53 but the instability is the major mechanism responsible for brain retention. The d,l-isomer of 99mTc- HMPAO shows prolonged brain retention, while the mesoisomer displays higher in vitro stability and little in vivo brain retention. 54 The unusual

"H" "H" [99mTc]Cyclam [99mTc]PnA O [99mTc]d,I-HM PAO [99mTc]meso-HMPAO

Fig 5. Chemical structures of sS"~rc-HMPAO and related complexes.


.. 'O:" "H . / / " / t

.," \ s

CH(CH3)2 [99mTc]BATO-2M P

Fig 6. Chemical structure of 99mTc-BATO.

instability of the d,l-isomer provides a mechanism for brain retention.

The third group of 99mTc-labeled brain perfusion imaging agents consists of boric acid adducts of technetium oximes (BATO) complexes (Fig 6). 5s'56 This class of neutral and lipid-soluble technetium complexes can be prepared by tem- plate synthesis: 99roTe pertechnetate is reduced by stannous chloride in the presence of vicinal dioximes under heating to produce the desired adduct. It is important to note that 99mTc-BATO complexes contain an ionizable chloride ion. When the chloride ion is detached from the complex, the net charge ranges from zero to plus one. The hydrolysis of the chloride ion may be an important factor in determining the biologic properties of these complexes. Several of these compounds exhibit myocardial and brain uptake reflecting regional perfusion. 5749 Initial brain imaging studies in humans appear to show the same distribution pattern as the other 99mTc agents; however, the exact mechanism of uptake and retention is unclear.

New 99mTc brain perfusion imaging agents are useful in detecting various cerebral vascular abnormalities such as stroke, transient ischemia and other neurological disorders (ie, Alzheimer's disease, 6~ epilepsy, 62 Parkinson's disease). 63'64 The exact trapping mechanisms and their rela- tionship with potential clinical applications still

remain to be investigated. However, initial clinical studies with 99mTc agents do show parallel clinical efficacy with that reported for the mI brain perfusion agents. It may require additional research to compare clinical interpretations when different 99mTc brain perfusion imaging agents are used (due to different uptake kinetics and trapping mechanisms).

CENTRAL NERVOUS SYSTEM RECEPTOR IMAGING AGENTS

In 1979 it was suggested that "radiotracers that bind to receptors may be a potential source of radiopharmaceuticals. ''65 In the past several years significant progress has been made in the design, synthesis, and characterization of new central nervous system (CNS) receptor imaging agents. A large number of positron emission tomography PET 66 and SPECT receptor 67 imaging agents have been reported. Among these radiopharmaceuticals, dopamine receptor imaging agents have been the subject of extensive studies. Not only is the dopaminergic system very important for daily function, it is also a possible primary action site for antiparkinsonian agents or neuroleptic drugs for schizophrenia. A wealth of pharmacological information is available about the dopamine receptors. 6871 On the basis of the coupling to adenylate cyclase activity and the differences of the action mechanism of agonists and antagonists, dopamine receptors can be di- vided into at least two subtypes: D-1 and D-2 receptors. 72'73 These two subtypes exert effects on the activity of CNS dopaminergic neurons. They influence each other and yet they display separate and distinct functions on physiology and biochemistry. 74-76

Several human CNS disorders, such as Parkin- son's disease, schizophrenia, tardive dyskinesia, and Huntington's chorea, involve changes to dopamine receptor density in the brain. 7779 The dopamine receptor imaging radiopharmaceuticals in conjunction with PET and SPECT provide a useful noninvasive tool in the evaluation of those various neurological disorders.

CNS D-2 Dopamine Receptor Imaging Agents

Spiperone derivatives. Several potential SPECT dopamine receptor imaging agents based on labeled spiperone derivatives have been reported. Attempts to prepare 123I-labeled spiper-

BRAIN RADIOPHARMACEUTICALS FOR SPECT

one were inspired by the successful D-2 dopamine receptor images of the human brain with N-nC-methylspiperone with PET. a~ Prelimi- nary studies of an iodinated 2'-iodo-spiperone (2'-ISP) (Fig 7) 82'83 indicated that the spiperone analogue displayed excellent D-2 specificity (Kd = 0.25 nmol/L in rat striatum) and in vivo stability compared with the 4-iodospiperone (Fig 7) 84 reported earlier. Recently, Mertens et al s5 reported the imaging studies of 2'-ISP in humans. Initial SPECT images showed less favor- able quality compared with those obtained by IBZM, a close analogue of raclopride. In addition, a new analogue of spiperone, N-iodoallyl spiperone (Fig 7), has been reported, s6.s7 The agent showed good striatum to cerebellum ratio in mice.

Benzamide derivatives. IBZM (Table 1) is a close analogue of raclopride, an antipsychotic agent (ltC-labeled raclopride is a useful ligand for PET). The preliminary binding studies showed specific binding of ~25I-IBZM in a striatum membrane preparation of rat brain with a kd value of 0.426 nmol/L. 8s The Bmax of this agent in the striatum of rats was 480 fmole/mg of protein, which was comparable to that reported in the literature using a similar procedure and 3H-spiperone as the ligand.S9 Biodistribution studies using autoradiographic techniques suggested that ~25I-IBZM was concentrated in rat striatum with high affinity to the D-2 dopamine receptors. 9~ In vivo planar imaging of the monkey showed significant brain uptake immediately after the intravenous injection of this agent. 8s

O 0 ~ / ~ ' N / R 1

R2

R1 R2 R3 Spiperone H H H N-Methyl-spiperone CH3 H H 2'-Iodo-spiperone (ISP) H H I N - I o d o a l l y l - s p i p e r o n e CH2CH=CHI H H 4-10do-spiperone H I H

Fig 7. Chemical structures of spiperone and related compounds.

295

Table 1. Chemical Structures and In Vitro Dissociation Constants of Benzamides

Compound R~ R 2 R 3 R4 Kd (nmol/L)

Raclopride OH CI CI OMe 1.1 Eticlopride OH CI Et OMe O. 17 IBZM OH I H OMe 0.43 Iodopride H I H OMe 10.2" Epidopride OH I OMe OMe 1.05* Ioxipride H I OMe OMe 0.92 IBF H I CH2CH20 O. 11

CON H C H ~ ' " " ~

* ICso value.

The ratios of the basal ganglia to cerebellum and the cortex to cerebellum were 4.93 and 1.44, respectively, at 2 hours postinjection. Phase I clinical studies of 123I-IBZM in humans con- firmed that this agent localized in the basal ganglia and to a lesser extent in the cortex and the cerebellum. 92 SPECT imaging in normal humans displayed specific regional uptake in the basal ganglia. 92

More recently, several newer iodinated benzamide derivatives, including iodopride, ioxipride, epidepride, spectramide, and iodobenzofuran, (IBF) have been reported. 93"9s In vivo biodistribution studies of ~25I-IBF in rats indicated that this agent concentrated in the striatum region and displayed a remarkably high target-to-nontarget ratio (striatum/cerebellum = 48 at 2 hours postinjection). 97 The in vitro binding studies suggested that IBF bound selectively to D-2 dopamine receptors with high affinity and low nonspecific binding (Kd = 0.106 nmol/L; Bmax = 448 fmole/mg protein). 97 Ultimately, the iodobenzamide series of compounds may provide a wide spectrum of affinity for CNS D-2 receptors as well as a different pattern of kinetic profiles for in vivo SPECT imaging.

Lisuride derivatives. Lisuride derivatives are another class of compounds that possesses D-2 dopamine receptor agonistic and antagonistic activity. Radioiodinated lisuride (Fig 8) has been prepared and reported to show good potential as a useful imaging agent for SPECT. 99q~ In vitro binding and in vivo autoradiography studies in

296 KUNG, OHMOMOoAND KUNG

H..,r

N\ Me

Fig 8. Chemical structure of iodolisuride.

rats demonstrated a high affinity (Kd ----- 0.27 nmol/L) and a high specificity for D-2 striatal dopamine receptors. 1~ In preliminary human studies, a clear delineation of the basal ganglia was obtained with SPECT at 1 hour postinjection of 123I-iodolisuride. The mean striatum-to- cortex ratio was 2.1 at 1 hour postinjection. 1~

Several significant CNS D-2 dopamine imaging agents for SPECT have been developed within the past several years. These agents provide powerful tools for exploring the cellular and receptor biochemical processes in vivo. In conjunction with SPECT, these new ligands have opened new insights in investigating neuroscience in vivo. They also provide a useful tool in the evaluation of various neurological diseases.

One major issue that remains unanswered on the SPECT methodology is the quantitation of D-2 dopamine receptors based on the SPECT images. A kinetic model of the uptake and retention of the agent in the basal ganglia region is needed in order to obtain quantitative information on receptor density. Since single-head SPECT requires a 30 to 60 minute data acquisition time, it is unlikely that more than one data point can be obtained. Dynamic scanning with dedicated SPECT may provide the kinetic data necessary for quantitating receptor density in the brain. With newer and faster SPECT equipment being introduced and additional research efforts being done on attenuation and scatter correction, the full potential of D-2 dopamine receptor quantification in nuclear medicine clinics may eventually be realized.

CNS l)-1 Dopamine Receptor Imaging Agents

SCH-23390 was the first highly selective central D-1 antagonist, s9"1~176 The corresponding Br-(SKF-83566) 1~ and I-(SCH-23982 or SKF-

103108A) 89'1~ compounds have also been shown to have a high specificity for central D-1 dopamine receptors (Table 2).

Several recent reports indicated that in conjunction with PET, [11C] SCH-23390 showed the highest concentration in the basal ganglia area of human brain. ]~ Based on these findings, several iodinated analogs were prepared: 123I-IBZP (SKF 103108 or SCH 23982); 123I-FISCH (4'-iodo- SCH-23390); and ]23I-TISCH (3'-iodo-SCH- 23390). 1~ An imaging study in a monkey using 123I-IBZP specifically for mapping of the CNS D-1 dopamine receptor demonstrated that the agent localized in the basal ganglia area, where D-1 receptor concentration is high. The results are comparable to those reported for N j 1C_methyl_SCH_23390.107,112 Because the iodo group of IBZP is next to a hydroxyl group, it is prone to in vivo deiodination. By moving the iodo group to a nonactive ring, as in FISCH, the in vivo deiodination is diminished. 11~ However, the affinity of this ligand to D- 1 receptors is lower compared with the parent compound, SCH- 23390 (Kd = 1.6 nmol/L v 0.3 nmol/L, respectively, in rat striatum membrane preparation). Results of the imaging study in monkey with 1231( _+)FISCH displayed a fast uptake, but also a rapid washout from the brain, leading to low target-to-nontarget ratio. H~ In order to increase the binding affinity and brain retention, TISCH was designed by Chumpradit (unpublished data, July 1990). The in vitro and in vivo data indicate that TISCH is an excellent D-1 dopamine receptor ligand with specific and selective affinity

Table 2. Chemical Structures and In Vi t ro Dissociation Constants of Benzazepines

Compound R 1 R2 Kd (nmol/L)

SCH-23390 CI H 0.3

SCH-83556 Br H 0.4

SCH-23892 (IBZP) I H 0.7 (+-) FISCH CI I 1.6 R-TISCH CI 3-1 0.2

R I " ~ / / N --CH 3 H ,,.. O" V H , ~

R2


Fig 9. Chemical structures of muscarinir receptor imaging agents IQNB and iodo-dexctimide.

N

I*

O / - O

(Kd = 0.2 nmol/L). 123I-TISCH is potentially useful for SPECT imaging of D-1 dopamine receptors in humans.

Muscarinic Acetylcholine Receptors

Muscarinic acetylcholine receptors play an important role in many physiological responses. Diseases such as Huntington's chorea and Alzhei- mer's dementia appear to involve changes in the density of this receptor. In normal humans the receptors are concentrated in the cortex and hippocampus, but not in the cerebellum.

An iodinated ligand for muscarinic acetylcholine receptors, (R)-3-quinuclidinyl-4-iodo-benzi- late (IQNB) (Fig 9) has been labeled with either 125I or with 123[.113-116 The binding of the ligand to the receptor is of high affinity (Kd = 0.02 nmol/L) and of high selectivity. 117 In vivo distribution in rats, cats, and dogs showed saturable uptake in the brain and the uptake can be blocked by cold carrier or the uniodinated QNB, supporting the finding that the biodistribution is receptor mediated. Another iodinated ligand, iododexetimide (Fig 9), has been synthesized and characterized. 117 This agent also showed promise as a useful agent for imaging muscarinic receptors.

SPECT images with IQNB in humans confirm the known biodistribution (by in vivo binding study of the post mortem samples) of this receptor in the CNS. H5 This agent has been shown to

be useful in evaluation of changes of muscarinic acetylcholine receptors in Alzheimer's patients.12~ Since the agent is very lipid soluble, in order to achieve a high target-to-nontarget ratio it is necessary to perform SPECT studies at 24 hours post-IV injection. The physical half-life of 123I, 13 hours, is relatively long, making this delayed imaging procedure feasible.

Benzodiazepine Receptors

Since their introduction for human use as anxiolytics and anticonvulsants in the 1950s, the benzodiazepines have been the most widely pre- scribed drugs. In the 1970s it was recognized that there was specific binding of the benzodiazepines by a single class of recognition sites in complex and thereby modulation of the gating of the chloride channel associated with the major inhib- itory amino acid transmitter receptor in the CNS. The receptor also exists in the peripheral nervous system. 121

Radiolabeled benzodiazepines (both agonists and antagonists) have been reported for PET imaging studies in humans. 12~ Several iodinated benzodiazepine derivatives have been reported in the literature: iodoflunitrazepan, 122 RO- 16-0154123'124 (Fig 10), and PK-11195) 25 The former two are CNS benzodiazepine receptors while the latter is for the peripheral system.

The iodinated compound, RO-16-0154, is a close analog of flumazenil (RO-15-1788), an

I o d o - f l u n i t r a z e p a m

[ ~ ~/~--- COOCH2CH3

l . "c.,

R O - 1 6 - 0 1 5 4 Fig 10. Chemical structures of

iodobenzodiazepine (R0-16-0154).


antagonis t tha t is used as an an t ido te in the t r e a t m e n t of benzodiazepine intoxicat ion. Brain images of RO-16-0154 indicate tha t the agent binds to the receptor in a specific and reversible fashion. 126'127 I t is possible tha t this agent m a y be useful to evalua te changes of receptor densi ty a n d / o r measur ing receptor occupancy re la ted to therapy .

BRAIN TUMOR IMAGING AGENTS

Imag ing of b ra in tumors with L-3-123I-iodo-a-

methyl - ty ros ine ( I M T ) (Fig 11) and S P E C T has been repor ted. 128'129 I t is genera l ly bel ieved tha t

b ra in tumors have a fas ter ra te of protein synthesis, which leads to an increased up take of amino acid in the region affected by the tumors. The observed increase in I M T up take in tumors is comparab le with tha t of l~C-labeled amino acids. However , HC amino acids a re incorpora ted into protein. The I M T , conversely, only uses the amino acid t r anspor t sys tem to cross the blood- bra in barr ier . A f t e r the bra in uptake , I M T is not incorpora ted into proteins. Therefore , ]z3I-IMT is a potent ia l ly useful imaging agent for bra in tumors , especial ly for mapping changes in amino acid up take in tumor cells.

. o

NH 2

I M T

Fig 11. Chemical structures of L-3-iodo-a-methyl- tyrosine.

CONCLUSION

In the past few years significant progress has been made in the development of new bra in perfusion and C N S receptor imaging agents for S P E C T . The new diagnost ic agents a re a imed at measurements of regional ce rebra l perfusion and local izat ion and changes of receptor densi ty. W i t h the ded ica ted S P E C T imaging devices being in t roduced commerc ia l ly , it is l ikely tha t these types of agents will achieve a widespread cl inical appl ica t ion in nuclear medic ine clinics.

ACKNOVVLEDGMENT

The authors thank Catherine Cartwright for her assistance in preparing this article.

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