Determination of Flow and Rate Constants in a Kinetic Model of [<sup>99m</sup>Tc]-Hexamethyl-Propylene Amine Oxime in the Human Brain

Oba, Hiroshi; Seki, Hidetoshi; Higashi, Sotaro; Sumiya, Hisashi; Tsuji, Shiro; Terada, Hitoshi; Imai, Keiko; Shiba, Kazuhiro; Mori, Hirofumi; Hisada, Kinichi

doi:10.1038/jcbfm.1988.34

Cited by 26 publications

(17 citation statements)

References 5 publications

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“…Higher values may be expected for white matter due to the high content of lipids in these regions. This is suggested by the studies of Matsuda et al (1988). In this context, it should be noted that the bolus injection experiments analyzed here are weighted towards the gray matter of the brain since it receives about 80% of the bolus (Ing var et al, 1965).…”

Section: The Modelmentioning

confidence: 84%

“…Therefore, as in the case when calculating the flow of whole brain (Andersen et aI., 1988c), one must measure not only Cj and A, but also Rj, in order to calculate the regional flow Fj in absolute units of mllg/min. Matsuda et al (1988) proposed to determine the local retention Fj using serial SPECT imaging as well as sampling of arterial blood. They assumed that Ej has the same value of 0.85 for all regions and the rate constants k2,j and k3,j could be determined for fairly large regions.…”

Section: General Considerationsmentioning

confidence: 99%

“…Their procedure in volves a deconvolution step but is otherwise closely related to the one we applied to the bolus injection studies. We propose to use a technically simpler approach than that of Matsuda et al (1988). This approach has been described in the third part of the theory section.…”

Section: General Considerationsmentioning

confidence: 99%

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The Retention of [^99mTc]-d,l-HM-PAO in the Human Brain after Intracarotid Bolus Injection: A Kinetic Analysis

Lassen

Andersen

Friberg

et al. 1988

J Cereb Blood Flow Metab

287

156

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Summary: [99mTcl-d,I-HM-PAO (HM-PAO) was injected rapidly into the internal carotid artery and its retention in the brain was recorded by external scintillation cameras in eight human subjects, A model is described based on three compartments: the lipophilic tracer in the blood pool of the brain, the lipophilic tracer inside the brain, and the hydrophilic form retained in the brain, The reten tion curve initially drops abruptly, corresponding to the nonextracted fraction of the injectate leaving the brain; it then falls exponentially towards the asymptotic level of the fractional steady-state retention R. Cerebral blood flow (F) was measured using the xenon-133 intracarotid injection method. The first-pass extraction E of HM-PAO was calculated from F using an empiric regression equa tion. The residue curves for the whole brain after intra carotid HM-PAO injection were analyzed to yield a re tention fraction (R') and the brain clearance backtlux con stant of lipophilic HM-PAO (k). From the kinetic model Technetium-99m forms a lipophilic complex with d,l-hexamethylpropyleneamine oxime (HM-PAO). This molecule was synthesized by Neirinckx and co-workers (N eirinckx et aI., 1987; N owotnik et aI., 1985) with the purpose of finding a tracer suitable for imaging cerebral blood flow (CBF) by single photon emission computerized tomography (SPECT). The molecule was selected from a long series of related molecules because of its prolonged retention in the brain in a pattern suggesting a flow dependent distribution.In the present paper, a kinetic analysis of the up take and retention of [99mTc]-d,I-HM-PAO in the Address correspondence and reprint requests to Dr. A. R. Andersen at Department of Neurology, N2081, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. S13and the measured values of R', k, and F, the following parameter values could be calculated: the average re tained fraction of all tracer supplied to the brain, R = 0.38 ± 0.05 (mean ± SD), the conversion rate constant (li pophilic to hydrophilic tracer) in the brain k3 = 0.80 ± 0.12 min -], the efflux rate constant (brain to blood) k2 = 0.69 ± 0.11 min -], the conversion/clearance ratio Ct = k3/ k2 = 1.18 ± 0.25, the influx (blood clearance) constant K] = 0.45 ± 0.11 ml/g/min, and the brainlblood partition ratio A = Kl/k2 = 0.67 ± 0.23 ml/g. Using the kinetic model and assuming constancy of Ct, an algorithm was developed that corrects for the blood flow dependent backflux of HM-PAO and results in a more linear relation between regional cerebral blood flow (rCBF) and HM PAO distribution. The kinetic model that we develop accounts for this conversion and yields a numerical value for the rate constant of the conversion process k3• This allows us to derive an algorithm that corrects the tomo graphic image for the backdiffusion of radiotracer from brain tissue to blood.

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Section: The Modelmentioning

confidence: 84%

Section: General Considerationsmentioning

confidence: 99%

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The Retention of [^99mTc]-d,l-HM-PAO in the Human Brain after Intracarotid Bolus Injection: A Kinetic Analysis

Lassen

Andersen

Friberg

et al. 1988

J Cereb Blood Flow Metab

287

156

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“…Here, x ¼ À F/PS and a ¼ À F r /PS are substituted into equation (6). As FEF r , the linear approximation (equation (6)) makes sense.…”

Section: Aðtþ Dt ð2þmentioning

confidence: 99%

Lassen's Equation is a Good Approximation of Permeability-Surface Model: New α Values for ^99mTc-HMPAO and ^99mTc-ECD

Kameyama

2014

J Cereb Blood Flow Metab

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Lassen's equation is a good approximation of permeability-surface model: new a values for 99m Tc-ECD Masashi KameyamaBrain perfusion tracers like [ 99m Tc] d,l-hexamethyl-propyeneamine oxime ( 99m Tc-HMPAO) and [ 99m Tc] ethyl-cysteinate dimer ( 99m Tc-ECD) underestimate regional cerebral blood flow (rCBF) at high flow values. To improve linearity between tracer accumulation and rCBF, two different models have been proposed. One is Lassen's correction algorithm for back-diffusion of tracer, and the other is based on the permeability-surface (PS) model for correction of low first-pass extraction. Although both these models have the same goal, they have completely different forms of equation. It was demonstrated that mathematical approximation of the PS model equation leads to Lassen's equation. In this process, the relationship between PS, CBF values and Lassen's parameter was acquired, and how to correct both the back-diffusion and low first-pass extraction was also demonstrated. A computer simulation confirmed that the two models provided similar consequences when the parameter value is chosen according to the relationship found. Lassen's equation can be used to correct not only back-diffusion but also low first-pass extraction. To perform overall correction, the parameter value we have been using for decades may be too weak. I estimated that the parameter value for overall correction of HMPAO would be around 0.5, and that of ECD would be around 0.65.

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“…In the brains of rats under pentobarbital anesthesia 19 and in normal patients, 20 Matsuda et al also demonstrated rCBF values determined with [ " r e ] HM-PAO significantly lower than those obtained with radiolabeled microspheres. These data also suggest that [""TcJHM-PAO acts like a chemical microsphere over only a limited range of blood flows.…”

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confidence: 99%

Regional cerebral blood flow and distribution of [99mTc]ethyl cysteinate dimer in nonhuman primates.

Orlandi

Crane

Platts

et al. 1990

Stroke

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Increases in regional cerebral blood flow have been described in a variety of cerebral pathologic states, including stroke and seizure disorders. The usefulness of technetium-99m-labeled cysteinate dimer as a marker in the measurement of regional cerebral blood flow was tested in five cynomolgus monkeys. To expand the range of blood flow to beyond the normal limits, 40 mg/kg i.v. of the carbonic anhydrase inhibitor acetazolamide was administered. Regional cerebral blood flow in all five monkeys was measured using radiolabeled microspheres (before and after acetazolamide) and the marker (after acetazolamide) in 60-70 samples from 12 brain regions. Acetazolamide significantly increased the mean±SEM regional cerebral blood flow measured using microspheres from 0.56±0.21 to 1.71 ±0.9 ml/min/g (p<0.01 for each region). A significant positive correlation was found between regional cerebral blood flow values calculated using microspheres and the marker after normalizing the values to those in the cerebellum (r=0.773, /?< 0.0001). The mean±SEM regional cerebral blood flow determined using the marker in a single monkey (1.21 ±0.04 ml/min/g) did not differ significantly from that determined in the same monkey using microspheres (1.13±0.04 ml/min/g). These data support the potential use of this new brain perfusion imaging agent to assess regional cerebral blood flow over a clinically relevant range of blood flows. It is widely acknowledged that in several pathologic states, such as focal ictal seizures, brain tumors, and stroke during the subacute phase, locally increased metabolic demands increase rCBF to beyond the range observed under normal conditions. 45 Similar increases in rCBF are also pharmacologically induced clinically with agents such as the carbonic anhydrase inhibitor acetazolamide. These pharmacologic stress tests have been extensively used to evaluate cerebral vascular reserve in stroke patients. Received December 11, 1989; accepted March 21, 1990. cate perfusion alterations for which surgical interventions may be appropriate. A linear relation between rCBF and [ 99m Tc]ECD retention over a clinically relevant range of blood flows is needed before we can employ this new radiopharmaceutical agent in high-flow pathologic states and stress studies. We studied the relation between rCBF as measured with radiolabeled microspheres and ["""TcJECD retention during acetazolamide-induced hyperemia in nonhuman primates to evaluate the cerebral distribution of ["TcJECD at blood flow levels beyond the normal range. Materials and MethodsFive adult, male cynomolgus monkeys weighing 3.6-10.3 kg were food-deprived for approximately 20 hours, and water was removed on the morning of the study. The monkeys were anesthetized with 10 mg/kg i.m. ketamine hydrochloride and 1 mg/kg i.m. acepromazine maleate. Anesthesia was then maintained with a constant infusion of 1.5 mg/ml i.v. thiamylal sodium (Parke-Davis, Morris Plains, N.J.) delivered through a 22-gauge catheter inserted into a saphenous vein at a rate averaging <0.5 ml/mi...

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Determination of Flow and Rate Constants in a Kinetic Model of [^99mTc]-Hexamethyl-Propylene Amine Oxime in the Human Brain

Cited by 26 publications

References 5 publications

The Retention of [^99mTc]-d,l-HM-PAO in the Human Brain after Intracarotid Bolus Injection: A Kinetic Analysis

The Retention of [^99mTc]-d,l-HM-PAO in the Human Brain after Intracarotid Bolus Injection: A Kinetic Analysis

Lassen's Equation is a Good Approximation of Permeability-Surface Model: New α Values for ^99mTc-HMPAO and ^99mTc-ECD

Regional cerebral blood flow and distribution of [99mTc]ethyl cysteinate dimer in nonhuman primates.

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Determination of Flow and Rate Constants in a Kinetic Model of [99mTc]-Hexamethyl-Propylene Amine Oxime in the Human Brain

Cited by 26 publications

References 5 publications

The Retention of [99mTc]-d,l-HM-PAO in the Human Brain after Intracarotid Bolus Injection: A Kinetic Analysis

The Retention of [99mTc]-d,l-HM-PAO in the Human Brain after Intracarotid Bolus Injection: A Kinetic Analysis

Lassen's Equation is a Good Approximation of Permeability-Surface Model: New α Values for 99mTc-HMPAO and 99mTc-ECD

Regional cerebral blood flow and distribution of [99mTc]ethyl cysteinate dimer in nonhuman primates.

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Product

Resources

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Determination of Flow and Rate Constants in a Kinetic Model of [^99mTc]-Hexamethyl-Propylene Amine Oxime in the Human Brain

The Retention of [^99mTc]-d,l-HM-PAO in the Human Brain after Intracarotid Bolus Injection: A Kinetic Analysis

The Retention of [^99mTc]-d,l-HM-PAO in the Human Brain after Intracarotid Bolus Injection: A Kinetic Analysis

Lassen's Equation is a Good Approximation of Permeability-Surface Model: New α Values for ^99mTc-HMPAO and ^99mTc-ECD