Downloaded from jnm.snmjournals.org by on April 17, 2018. For personal use only.
Cerebral Perfusion Imaging Tracers for SPECT: Which One to Choose? J.L. Moretti, M. Caglar and P. Weinmann HopitalAvicenne,
CHU Leonard
de Vsni4 Bob@zy,
France
ticals, since correlation
J NuciMed1995;36:359-363
caused
R
found between
PET or micro
spheres and SPEC!' blood flow agents has demonstrated that the relationship is curvilinear. Recently, several re searchers suggested that the rising asymptotic plateau is by washout
from high-flow
regions
(3,4). The up
take, extraction fraction and retention of the agents used adionucide imagingand semiquantitationof cerebral vaiy among different regions of normal and abnormal brain perfusion by SPEC!' are important issues in patients (1) and the fixation can be altered by local or regional
with neurological and psychiatric diseases. The search for
an ideal brain SPECT radiopharmaceuticalis complicated and competes with other imaging modalities such as dy namic CT and MRI. Unfortunately, radiopharmaceuticals
currently
available
are far from ideal.
The ideal agent should be commercially available, easy to label, possess in vivo and in vitro stability, have short arterialinput to facilitate intervention (stimulation)studies and a high extraction fraction at the first pass. Such an agent should reach a steady state in the brain quickly and be able to penetrate intact blood-brain barriers regardless of the blood cell-plasma protein partition. They also must have high passive retention in the brain independent of a metabolic or enzymatic system or a specific binding site.
An ideal agent would also reflect regional distribution, which is linear to the cerebral blood flow over a wide range
and remain fixed in the brain with a constant pattern to permit SPECT imaging with minimal extra brain activity.
The ideal radiopharmaceutical should be neutral, ii pophilic (log p octanol/water between 1.0—2.5) and of small size (under 500 dalton) (1). All of the technetium-amines
andiodo-amines discussed in this editorial[hexemethylpro pyleneamine
oxime
(HMPAO),
bicisate
(1,1-ECD)
or iso
propyl iodoamphatamine (IMP)J meet these criteria at different levels oflipophilicity, which determines biodistri
parameters.
The kinetic behavior and trapping mechanism
specific to each tracer must be well understood for the cm ical application and interpretation of SPECT images. Tech netium-99m-d,1HMPAO (exametazime) and @Fc-1,1 ECD (bicisate) are both available and easy to label, however, HMPAO has poor in vitro stability (RP = 85% after 30 min)
(5) and susceptibility to radiolysis, whereas ECD is much morestable(RP = 96%at6 hr)(6). These technetium-amines demonstrate in vivo instability following blood contact and have a short arterialinput of the bioavailable compound (7-9). The moiety of compoundschangesin circulating blood, which results in relative'y poor extraction (E) by the brain (HMPAO 77%, ECD 60%) (Table 1). The retention in the brain parenchymais linked to the enzymatic reactions with glutathione (GSH) for HMPAO (10,11) and with ste reospecific deesterification to acid derivatives for ECD (12— 15). These mechanisms have slow turnover and yield non diffusible polar metabolites. The first-passextractionrate is flow-dependentfor ECD, similar to HMPAO, and results in decreased uptake in the
higher flow of a normal range (16). Conversely, extraction is higherwhen the flow is reduced. Due to a low backflux from brain (k2), the retention of ECD is higher than HMPAO (Table 1). Backdiffusionof HMPAO is more pro
bution. At higher levels of lipophilicity, there is a trade-off nounced in high flow regions and a higher extraction in low flow regions results in poor contrast. Technetium-99mbetween binding to the brain cells and plasma proteins in favor of the latter (2). A @‘Fc-labeled compound that ECD images hold a slightly better contrast between high and low flow regions. ECD has some washout from the behaves like IMP would represent a major advance for routinebrainperfusionimaging.However, a consensus has not yet been reached on the best agent. A clear understandingof the absence of a true flow agent is crucial before comparingthe available radiopharmaceu ReceivedOct 18,1994;acceptedOct.24,1995. Forcorrespondence orreprints onnt@Jean-LieMcmlii,MD,PhD,Med@ine Nucieaire, Ho@ Avicenne,99009Bobigny,France.
Cerebral Pertu@on Imaging TracesforSPECT• Morethetal.
brain and negligible redistribution
(17,18). HMPAO
has
slow clearance and liver accumulation contrary to ECD, which has rapid blood clearance with renal excretion of acid metabolites (EC) yielding a better signal-to-noise ratio.
IMP, which is not readily available in every country and is cumbersome to label, was the first iodo-amine (19) used for brain imaging with a high brain extraction rate (96%)
359
Downloaded from jnm.snmjournals.org by on April 17, 2018. For personal use only. TABLE I
nism and metabolism of the tracer. This washin/washout
Comparison ofBrainSPECTImaging Agents
balance is clearly demonstrated in the study performed by
Nishizawa et al. (24) who CharecteristlcIMPHMPAOECDLogP1.401.901.64Purity96%85%96%Stabllfty6hr30mm6hrHead radioactivity
observed a temporal change of
among normal brain structures.
Likewise,
IMP uptake is different between white and gray matter and favors the latter. The first possible explanation 1.9BUI1137773E%907760ki0.430.26 uptake (%lD)6.0 ±15.2
±16.3
0.25tk20.0140.60*
0.27t0.29
0.19tA
0.59t0.22
±
for this is
the first come, first served principle. Since the penetrating capillaries enter the gray matter, more tracer is available to be extracted by gray matter before reaching the white matter. The second explanation is the difference in the extraction coefficient of IMP between gray and white mat
ter (21). Rapinet al. demonstratedby autoradiographythat the activity in the brain redistributeswith time in favor of the white matter possibly due to backflux from gray to
=
[email protected]* 0.31tk30.930.58*
0.46t1.31*
O.59@a
[email protected]
white matter (25). For this reason, it is crucial to perform
early imaging at 20 min. Afterwards, polar metabolites such as p-iodobenzoic acid (PIBA) will appear in the 3.l@R%98%50%@ 0.9r2.6@ plasma in non-negligible amounts with time (26), diffusing 75%tE%88365k 49%t72% passively through a damaged blood-brain barrier. There fore the delayed images have to be acquired at 3 hr. 45tK0.420.13* 37.7k43.2* One of the most active and exciting fields of nuclear medicine has been evaluating cerebral perfusion in several O.l9@RediStributiOn++100t(mln)201010Meanwashoutrateof1%2%10%steady
[email protected]* k2ik3700.9r
pathologies. There are certain conditions where different
lipophilic tracers give similar images such as drug addic tion, dementia, interictal epilepsy, psychiatric disorders
(hr)Heterogeneous state washout
+
+
0
and head
trauma.
Ictal,
postictal
epilepsy,
stimulations
and
stroke are not among these conditions.
*SeeReferences49,50and51. SeeReference48for IMPdata tSee References16 and 51. kl = unidirectIonal influxconstantcorrespordngtoflowx extraction (firstpass)(Fx g1m@1;@=back-flwinh/rT@,k1/k2=pardtion
@e1ficient inthecoitex@ k3 = transformation constant(1/mm),a =
@
conversion
rate,
R
=
retention
state influxconstant = K1.
fr@ion
=
k3/k2
+
k3,
K
=
ICTAL AND POSflCTAL EPILEPSY
Interictal perfusion SPECT was performed with iodoam k3@2 ines (27) andTc-amines (28)yielding a sensitivity of 60%to
steady
+ K@,/ E = extr@ion at first pass, E =
E*R Extraction at steadystate,BUI = bran u@akeindex@ logP = dedmaiioga@thm ofthe partitioncoefficientoctanolonwater,t = timeto reachthesteadystate,W = washoutrateaftersteadystate(hr1) from brain.
75%whichcorrelates wellwithEEGstereolocalization.
Fluctuations in perfusion and metabolism in the interictal period do not allow the detection of more than 75% epilep tic hypoactive foci with perfusion SPECF or FDG-PET (29). During the ictal phase, higher metabolic activity cou pled with high perfusion results in increased uptake in the epileptic foci. True ictal studies are difficult to perform in
(Table 1). Its uptake linearly follows a wide range of flow assessed by microspheres (20). The gradual increase in the brain uptake of IMP (50% at 5 miii and 90% at 20 min) is linked to its clearance from the lung, which functions as a buffer releasing the tracer into the circulation
(21). The
stereoselective retention mechanism of IMP in brain tissue involves a possible conversion to hydrophilic metabolites (22), and an affinity to high capacity and relatively nonspe cific binding sites. Intracellular pH can play a role in many instances: (1) rate of exchange through the BBB; (2) strength of binding to the nonspecific sites of the brain; and
(3) metabolic conversion rate of aminesthrough the enzy matic system linked with binding sites. When blood pH is
vitro with unstable HMPAO, rendering it impossible to store in the neurology department. In this case, com pounds of higher stability such as IMP or ECD are more
appropriate. In the early postictal phase, cerebral blood flow remains elevated decoupling from the rapidly dccliii ing glucose metabolism (30). Blood flow remains elevated long enough to allow lipophilictracers to detect the hyper active foci. Since ECD has a shorter arterial input, it ap
pears to be more appropriate than IMP. Sensitivity in creases by 10% during the immediate postictal phase (31).
S11MULA11ON In normal cerebral autoregulation, cerebral blood flow
decreased due to local lactate discharge, the uptake of IMP is notably decreased (23).
increases in response to neuronal metabolism; SPED.' has demonstrated sufficient sensitivity to detect changes in ac
Brainretention of IMP reflects the balance of the washin andwashout ofthe tracerin individualstructures. Washout from brain is influenced by blood flow, retention mecha
tivity related to stimulation of metabolic activity (32). These activation tasks must generate detectable and repro
360
ducible changes in cerebral blood flow which are sustained
TheJournal ofNuclear Mediane • Vol.36• No.3 • March1995
Downloaded from jnm.snmjournals.org by on April 17, 2018. For personal use only.
during the period after injection, while the tracer reaches steady state. In the activation studies, the tracer distribu tion has to reflect high flow rates, like IMP, in order to
flow is inadequaterelative to the energy/metabolicdemand for oxygen and substrate (misery perfusion). In these in
quantify the stimulation accurately.
cause retention in the pen-infarctzone. The only definitive
The trapping process
stances,
slower metabolism
and washout
of IMP would
of the tracer should not be saturable in test/retest studies
conclusions made on redistribution IMP SPEC!' images is
using split dose technique within a short interval. In the test/retest studies, assumption is that the original distribu
whether non-necrotic cells are present or not. The redis
tion pattern is still the same during the second SPECF image acquiredafteractivationon the same day. Due to the heterogeneous washout pattern, a test/retest protocol would introduce significant errors, therefore a two day protocol is preferable (33). As the radioactivity of d,1 HMPAO changes with time after preparation(in vitro and in vivo), even if equal doses of radioactivity are injected, one cannot be sure of the same bioavailabiity for brain. Using HMPAO in a test/ retest activation study requires a long stimulation of the same intensity. ECD has the same uptake and retention characteristics of HMPAO, but it is more stable and more convenient to handle. Like HMPAO, however it underes
outcome (39). With ECD in the acute phase of stroke, when the ester ase enzyme system is still functioning, a higher extraction and retention of the tracer results in low blood flow areas (40). In the subacute phase, hypoxia may alter the function of esterase, resulting in minimal retention, even if the ex
timates high flow areas (5).
tribution of IMP was formerly related to a good clinical
traction is preserved. The hypoactive area will be larger
and deeper on delayed images, demonstrating increased clearance from the ischemic areas (41,42). Diminished ac tivity of ECD in subacute
stroke may be due to the lack of
oxygen and enzyme activity, which causes an accumula
tion of unmetabolizedtracercandidate to leak out from the peripheral ischemic zone. By contrast, at low blood flow,
since the GSH system is more resistant to hypoxia and continues to function, cells retain HMPAO in the ischemic
area. During the period of luxury perfusion after recanaliza Tomographic images of cerebral perfusion with 11- tion, there is transientdecouplingof metabolic demandand pophilic radiotracers are extremely useful in early detec cerebral blood flow in the subacute phase of ischemic re tion of acute and chronic stroke. SPECF is superiorto Cl' gions. Increased glucose consumption is observed, indicating in detecting ischemia since it reflects alterations in perfu anaerobic glycolysis and production of lactate accompanied theuptakeof IMP.In sion before structuralchanges occur. This is an advantage by localacidosisallofwhichdecrease for determining the appropriate therapy, which must be this condition, the behavior of the perfusion tracers is differ ent. Most of the time HMPAO shows a focal areaof hyper initiated as early as possible in acute stroke. In stroke, two differentiatedregions are observed in the activity, whereas IMP and ECD demonstrate hypoactive brain: one the central infarct core known as the structural zones and IMP is relatedto low extractionin acidic pH and abnormality, which can be imaged by CF and two a pe ECD caused by low retention, which is linked to altered ripheralarea that reflects pen-infarct ischemia, known as esterase function in hypoxia (43,44). the penumbral zone (34). SPECT perfusion imaging can In reversible ischemic stroke, structuralimaginghas lit demonstrate both of these regions depending on the tracer lie to offer and perfusion imaginghas low sensitivity (60% used. There is a correlation between the penumbralzone within the first 24 hr (45), declining further with time). To and the severity of the neurological deficit which may be increase sensitivity, it is necessary to assess vasodilatory related to outcome (35). reserve by an acetazolamide stimulation test as demon Because of the high extraction rate in low-flow regions strated by us with IMP (46,47). The weak contrast ob and the high level of perfusion in ischemic regions due to tamed with HMPAO and ECD in very mild ischemia is a CEREBROVASCULARDISEASE
vasodilation,
HMPAO cannot be reliable to detect peri
infarct ischemia in the subacute phase (4—15 days). If im ages are acquired at 4 hr, clearance of the plasma activity and leakage of the tracer from the cells allows imagingof hypoactive peri-infarct ischemia (36). On the contrary, early IMP images demonstrate both structural abnormali ties (40% decrease) and the penumbral zone (15% de crease). With time, even if the central area remains un changed, redistribution occurs in the peripheral zone resulting in a partiallyfilled delayed images. The degree of redistribution is correlated with the local cerebral blood
flow and regional consumption of oxygen but not with the regional oxygen extraction fraction which reflects viability (37). IMP redistribution indicates a tissue with low CBF and a remainingmetabolism (38). This implies that blood
Cerebral Perfusion ImagingTraces for SPECT • Morettiat al.
drawback incorrectly delineating lesions. Because activity
of these @“@Tc-labeled amines is not linear at high flow rates, the response to acetazolamide is blunted as is lesion contrast. CONCLUSION Although IMP because of its linearity with flow and
capacity to depict mild ischemic regions seems to remain the reference in assessing cerebrovascular diseases, ECD, due to its availability and improved stability, will likely become widely used even though it is far from being an
ideal chemical microsphere agent. Technetium-99m-ECD is a powerful diagnostic tool to facilitate critical manage ment decisions in neurologic and psychiatric diseases. It is
361
Downloaded from jnm.snmjournals.org by on April 17, 2018. For personal use only. necessary to be cautious, however, in using this tracer in extreme conditions oflow and high brain blood flow and in
test/retest examinations. Iodune-123-IMPhas not been re placed by Tc-labeled amines. The search continues for an optimal brain tracer of perfusion and viability as a reliable
first step for functional and receptor imaging. Although the task to find the ideal agent is difficult, the challenge is worthwhile. With early diagnosis of cerebrovascular dis ease, there is an opportunity for improved outcome.
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Scatter (Continuedfrom page3A)
development of ‘231-MIBG, ‘ ‘ In-pentetreotideor otherreceptor-specificradiolabeledligands. I did not tell them ofthe men and women who work in the middle ofthe night to produceand deliver those magic bullets, or ofthose who work day after day in hospitals and offices obtaining images and data. Nor did I describe the wonder ofa gamma camera or my delight
when watching three-dimensionalimage acquisition,volume reconstructionand fusion with
MRIor CT images.Thereis neverenoughtimeto relatethe fascinationofwatchingthebrain think,the heartpump,or themarvelsof otherorganfunction. Nuclear medicine is more than a medical specialty. It is a wonder to behold. Stanley J. Goldsmith, MD, Editor-in-Chief TheJournalofNuclearMedicine —March 1995
CerebralPerfusionImagingTracesfor SPECT• Morethet al.
363
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Cerebral Perfusion Imaging Tracers for SPECT: Which One to Choose? J.L. Moretti, M. Caglar and P. Weinmann J Nucl Med. 1995;36:359-363.
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