Myocardial imaging in man with I-123 meta-iodobenzylguanidine, RC Kline, DP Swanson, DM Wieland

Tags: IBG, count rate, bolus, thyroid, thin layer chromatography, interpolation technique, laboratory screening, laboratory screening panel, Cardiac imaging, sodium acetate, electrocardiogram, specific activity, myocardial perfusion, binding agents, subjects, gamma camera, norepinephrine
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MyocardialImagingin Man with I-123 Meta-Iodobenzylguanidine
Robert C. Kline, Dennis P. Swanson, Donald M. Wieland, James H. Thrall, Milton D. @OSBSe, rtram Pitt, and William H. Beierwaltes University of Michigan Medical Center, Ann Arbor, Michigan Meta-[1231]Iodobenzylguanidine (m-I1231J1BG),a guanethidine analog, was used to image the myocardiumin five normalmale volunteers.Each subjectreceived 2.0 mCi m-[123lJlBG intravenously. Four were given a bolus Injection. Multiple myo cardIal sclntigramswere obtainedover a 2-hr period.Myocardialuptake was cal culated by dividingthe decay-correctedglobalmyocardialCOuntrate (after inter polatedbackgroundcorrection)by the peak countrate duringthe first passageof the m-[123l]IBGbolusthroughthe head. The left ventriclecouldbe visualizedwith in 1-2 mm of m-[[email protected] myocardialuptake was 0.63% (range 0.45-0.78 %) of injected dose at 5 mm, and 0.76% (range 0.49-0.93 % ) at 2 hr (n = 4).m-I123lJmlBaGyprovidqeuantitatiinvfeormatoionnmyocardciaatlechol amine content. J NuclMed 22:129в"113928,1
Tracer studies in animals with norepinephnine la
beled with H-3 or C-14 have shown its rapid localization
in the heart (1,2). Since myocardial norepinephnine
concentration is altered in a variety of pathologic con
ditions (3), myocardial imaging with norepinephrine or
a norepinephrine analog could prove to be of consider
able diagnostic utility. Carbon-I I norepinephnine has
been used to image the canine myocardium (4), but the
use of such an agent is limited by the need for both a
cyclotron and a positron camera on site. An agent that
is more readily available and is compatible with con
ventional single-photon cameras would be of greater
practical use.
I 231]iodobenzylguanidine
I 231]IBG), an
analog of the adrenengic-neuron-blocking agent guan
ethidine (Fig. I), has recently been used to image the
heart in the dog and the rhesus monkey (5). The mech
anism of uptake has not been fully elucidated, but initial
studies suggest that m-[1231]IBG may be stored in ad
renergic neurons by the same mechanism as that for
norepinephnine (5). We report our initial use of this
agent in five normal human volunteers.
METHODS Iodine-l23 produced by the 1271(p,5n) в~23Xвe"1231 reaction was obtained commercially.t Meta-['231]io dobenzylguanidine (m-['231]IBG) was prepared by a method similar to that reported for meta-['251]iodo benzylguanidine (6). The final product was formulated in bacteniostatic 0.9% saline, buffered to pH 6.0 with NOREPINEPHRff'JE N'H Nв"CH2CHN2HN2H-C- GUANETHIDINE [email protected] [email protected]
ReceivedSept.5, 1980;revisionacceptedNov. 6, 1980. For reprintscontact:RobertC. Kline, MD, Div. of Nuclear Medi cine, Univ. of Michigan Medical Ctr., 1045 E. Ann St., Ann Arbor, MI 48109.
I M-IBG FIG. t chemical structures of noreplnephrine, guanethidlne, and m-IBG.
Volume 22, Number 2
KLINE. Swanson. WIELANL). TIIRALL. GROSS. PlI r. AND [email protected]@RWAl.lES
sodium acetate. Radionuclidic purity, determined using a low-energy, lithium-drifted germanium gamma de tector, was always greater than 99% at calibration. Free iodide content was always less than 2%, as assessed by radioactive thin layer chromatography (silica gel G with ethyl acetate:ethanol, 1:1). specific activity averaged 5.0 mCi/mg at a calibration time immediately after syn thesis. Tests for pyrogens and bacterial contamination were uniformly negative. informed consent was obtained from five male vol unteers, ages 23-31 yr. All were normal by history, physical examination, electrocardiogram, and laboratory screening panel. To block thyroidal uptake of free 1-123, all were given Lugol's solution U.S.P., three drops twice daily, for 1 day before and 2 days after imaging. Vital signs and electrocardiograms were monitored before, during, and after injection of the tracer. Electrocardio grams and laboratory screening panels were repeated 24 hr after m-['23lJlBG injection. Each subject was given 2.0 mCi m-['23l]IBG by an tecubital vein. Four were given the dose as a bolus. All data were recorded onto a dedicated nuclear medicine minicomputer for display, video formatting, and quan titative analysis. Cardiac imaging was performed in a 400 left anterior oblique projection, using a standard field gamma camera equipped with a low-energy, high-sensitivity collimator. A 25% window was used, centered at 159 keV. A 60-sec dynamic acquisition at one frame/sec was begun simultaneously with the m [в~231]IBGinjection. Five-minute images were acquired sequentially for 60 mm, and again at 90 and I 20 mm. Additional 50,000-count images were obtained on a wide-field gamma camera with pinhole collimation. From the initial 60-sec flowstudy, time-activity curves were generated from the entire detector field of view except the outer three pixels (to avoid edge packing). The curves were inspected in conjunction with the images to determine the count rate during the frame with maxi mum activity in the heart. This count rate was taken to represent I00% of the injected dose. Background correction of static images was obtained using the interpolation technique described by Gonis (7)
Thyroidt Adrenal medulla Ovary (testes) Liver Pancreas Spleen Kidney Heart Wholebody
2.18 0.82 0.06 0.05 0.07 0.14 0.05 0.03 0.03
. Basedon dogdistributionstudies.
t Assume
t Data for unblocked thyroid. Radiation dose to thyroid
resuftingfrom 1-123as Iodide,liberatedin vivo, will be further
reducedbyadministrationof Lugol'siodine.
and modified by Watson and Beller (8). Myocardial
percent uptake was calculated by dividing the decay
corrected net myocardial count rate following back
ground correction by the count rate during the first
passage of the m-['231J1BG bolus. Since the technique
is not applicable with a poor bolus, the images and curves were inspected to ensure adequacy of the bolus as it
reached the heart. Each of the four subjects studied in
this fashion received a compact bolus. Heart-to-lung and
heart-to-liver ratios were calculated from normalized
regions of interest selected by light pen from the un
processed images.
To determine the elimination kinetics of m-['231J1BG,
blood, urine, and feces were collected at preselected in
tervals and analyzed for radioactivity. Radiation do
simetry estimates (Table 1), initially calculated from
animal distribution studies using m-IBG tagged with 1-125and 1-131(9), were modifiedfor the heart and
whole body according to human uptake and clearance
The left-ventricular myocardium could be visualized
FIG. 2. m-I1231JIBGimages of myocardium in five normal volunteers,acquired over 15 mm in the 40В°LAO projection. (A) unprocessed digital images.(B) images after interpolated backgroundsubtraction.
80. вў вў
@.60 вў
0c3 ввў ў
@.40 вў
5l5 30
TIME (minutes)
FIG. 3. Myocardialpercent-of-doseuptakeof m-[1231]IBGinfour normal subjects for first 2 hr after Injection. See text for deriva tion.
FIG. 5. @[[email protected] of myocardiumin normalvolunteer, acquired 135 mm after Injection (pinhole collimator, for 50,000 counts in 40В°LAOprojection).
within 1в"2mm ofm-['231]IBG injection. Uptake in the upper septum and base appeared less than in other wall segments, and apical thinning was prominent in two subjects. Otherwise the images (Fig. 2) were qualita tively similar to those produced by perfusion agents. Mean myocardialuptake was 0.63%(range 0.45-0.78%) of injected dose at 5 mm, increasing to 0.76% (range
I .68% of the injected dose. Estimated radiation dosim etry based upon the human distribution data for m [в~23IJIBGwas 0.03 rad/mCi for the heart and 0.03 rad/mCi for the whole body. DISCUSSION
0.49-0.93%) at 2 hr (n = 4, Fig. 3). Mean heart-to-lung
This study demonstrates that
ratio was I . 17 at 5 mm, increasing to I .44 at 2 hr (Fig. guanidine (m-['231]IBG) can be used for myocardial 4A), and the corresponding heart-to-liver ratios were imaging in man. The clinical role ofthis new radiotracer
0.78 and 0.60 (Fig. 4B). Images obtained with a pinhole remains to be defined. Our goal is not to develop a re
collimator at 135 mm showed significantly improved placement for the perfusion agent Ti -201 , but to explore
target-to-background (Fig. 5).
the possibility that m-[1231]IBG uptake can be used to
No significant side effects from m-['23111BG ad reflect myocardial catecholamine content quantitatively.
ministration were encountered. One subject noted a so, the agent could prove useful in the evaluation of
transient (в[email protected]вc)"5feeling of lightheadedness when the such conditions as congestive heart failure, ventricular
bolus was injected, and another reported a brief metallic hypertrophy, autonomic denervation, and hyperthy
taste. No changes in cardiac rhythm or vital signs were roidism, all ofwhich have altered myocardial catechol
found in any subject. Repeat electrocardiogram and amine stores (3). Before such applications can be at
laboratory test panel at 24 hr remained normal in all tempted, the dependence of m-['23lJlBG images on
myocardial perfusion, nonspecific uptake, and specific
Blood clearance of m-['231]IBG was rapid (Fig. 6). norepinephrine-like
uptake must be determined as
Mean urinary excretion was 64% (range 53-70%) over functions of time.
the first 24 hr (Fig. 7). Twenty-four-hour fecal collec Other investigators have reported upon the potential
tions, obtained in two subjects, contained 0.06% and of radiolabeled beta-adrenergic-receptor binding agents
for myocardial imaging (10). Application ofthese agents
has been difficult because successful imaging requires
A I .4 S
::[email protected] 0 V :@
515 30
TIME (minutes) @ FIG. 4. (A) heart-to-lung ratios for m-I1231JIBGin five normal subjectsfor first2 hr after injectiond, erivedfromselectedregions
[email protected] 5 5 30
[email protected] в[email protected]
TIME (minutes)
of interest in unprocesseddigital images. (B) heart-to-liver ratios FIG. 6. BlOOdclearance m-[12311IBGin five normal subjects.(Bars
for ,fl.[123I][email protected] in(A). (Barsshows.e.m.)
show s.e.m.)
Volume 22, Number 2
60 w U) g 20
TIME (minutes)
FIG. 7. CumulatIveurinaryexcretion of m.['23lJlBG In five normal subjects.(Barsshows.e.m.)
t Crocker Nuclear Laboratory, Davis, CA. ACKNOWLEDO M ENTS This work wassupportedin part by NIH Grant No. I-P0-I-NS 15655-01, DOE Grant No. EY-76-S-02-2031, NCI Grant No. CA 09015-05,and NIH Grant No. l-R0l-AM-21477-02. The authors thank Thomas J. Mangncr and Holly Anderson-Davis for synthesizing m-I'23lIlBG; Kathleen Worthington, and Laura Meyers for their technical assistance; Linder Markham for her help in preparing this manuscript; and John D. Jones and Dr. William Kerr for the use of their laboratories in the Phoenix Memorial Labora tory.
compounds with very high specific activity in order to
avoid saturation of binding sites having high affinity but
low capacity. In contrast, since the catecholamine stor
age vesicles have a very high capacity, a radiopharma
ceutical with the same storage pattern as norepinephrine
could be a successful imaging agent without satisfying
such stringent requirements for high specific activity.
Accurate quantitation of myocardial uptake is critical
to the ultimate clinical application ofm-['231]IBG. Our
method for calculating uptake assumes that (a) all the
initially injected activity is within the region of interest
selected over the chest for determination of the I00%
injected dose value; (b) internal distribution is such that
attenuation is similar for the bolus and the delayed im
ages; (c) background can be subtracted with acceptable
accuracy; and (d) camera deadtime is not a significant
factor. As the procedure has been performed, a compact
bolus satisfies conditions (a) and (b). The interpolated
Background Subtraction technique is felt to be the best
method currently available for meeting condition (c).
Finally, the 2-mCi bolus results in negligible deadtime
with the modern gamma camera, satisfying condition
(d). In summary,m-['23lllBG isa newagentfor human
myocardial imaging that may provide quantitative in
formation on myocardial catecholamine content. With
its I- I 23 label, this radiopharmaceutical
can be used
without special equipment in a typical nuclear medicine
I. WHITBY LG, AXELROD J, WEIL-MALHERBE H: The fate of H3-norepinephrine in animals. J Pharmacol Exp Ther
2. K0PIN IJ,G0RD0N EK, HORST D: Determinants of tissue
uptake of norepinephrine(NE). Fed Proc 23:349, 1964
3. WURTMAN RJ: Catecholan,inesB. oston,Little Brownand Company, 1966, pp6l-lOO
4. FOWLER JS, WOLF AP, CHRISTMAN DR. et al: Carrier-free
I в~C-labeled catecholamines. In Radiopharmaceuticals.
bramanianG, RhodesBA, CooperJT, SoddVi, Eds.New
York, The Societyof Nuclear Medicine, I 975, pp 196-204 5. WIELANDDM, BROWNLE, ROGERSWL, etal: Myocar
dial imaging with a radioiodinated norepinephrine storage analog. J NucI Med 22:22-3 1, I 981
6. WIELAND DM, Wu J-L, BROWN LE, et al: Radiolabeled
adrenergicneuronblockingagentsA: drenomedullaryimaging
with [в~3tljiodobenzylguanidine. J Nuc! Med 21:349-353, 1980 7. GoRis ML, DASPIT5G. al: Interpo lative backgroundsubtraction.J NucI Med I 7:744-747, 1976
8. WATSON DD, CAMPBELL NP, BERGER BC, et al: Quanti tation ofTl-20l myocardialdistribution and washout:Normal
standards for graded exercise studies. Am J Cardiol 45:480, 1980 (abst)
9. SWANSON DP, CAREY JE, BROWN LE, et al: Human ab sorbeddosecalculationsfor iodine-I 31and iodine-I 23 labeled
meta-iodobenzylguanidine (mlBG): A potential myocardial and adrenal medulla imaging agent. Proceedingsofthe Third
International Symposium on Radiopharmaceutical Do simetry. in press
10. JIANG VW, GIBSON RE, RZESZOTARSKIWi, et al: Ra dioiodinated derivatives of f3-adrenoceptorblockers for
myocardial imaging. J Nuci Med I 9:9 18-924, 1978
NUCLEAR MEDICINE HOTLINE A Hotline is available for technologistslooking for positionsand for employersseekingapplicants inthegreater New Yorkarea.The вoeHotlinise:в· (516) 679-9268 Physicians interested In employment, or those seeking employees, should contact Dr. Philip Bardfeld at: (516) 542-2674. Physicists and radiochemists should contact Dr. Marilyn Noz at: (212) 679-3200, ext. 3638.
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