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

Abstract

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.

99mTc-d,l-HMPAO and SPECT of the Brain in Normal Aging

“…Quantitative studies have been performed previ ously in patients with a variety of diagnoses and validated against results obtained with 133Xe inha lation technique (Andersen et aI., 1988a) or mea surements with PET (Inugami et aI., 1988;Yonekura et aI., 1988). We used the correction al gorithm of Lassen et al (1988), which is a simpler approach for quantitation of rCBF using 99mTc_ d,l-HMPAO. The algorithm was used to normalize to the cerebellum and to correct for the initial pref erential back-diffusion of d,l-HMPAO from high flow regions.…”

“…The pixels representing cerebellar tissue were defined from the posterior part of this slice by a computerized procedure using a lower 60% frac tile threshold value and allowing the mean count rate in each cerebellar hemisphere to be calculated. The higher of the two cerebellum values was used as the C r e f ' To calculate the relative flow value F (%) and to correct for incomplete retention of the tracer, the linearization algorithm suggested by Lassen et al (1988) was applied pixel by pixel to all images, using a conversion-to-clearance ratio ex of 1.5:…”

Human Regional Cerebral Blood Flow during Rapid-Eye-Movement Sleep

“…The two sets of distribution images were normalized relative to the mean count rate in their respective cere bellar regions and then linearized according to the algo rithm described by Lassen et al (1988) in an attempt to restore count rates in high-perfusion areas.…”

Extraction of [99mTc]—d,l-HM-PAO across the Blood—Brain Barrier

“…4 ml/g/min CBF jected bolus in brain capillaries. Since backdiffusion also appears to be blood flow dependent and is greater at high flows, the errors in CBF estimation using HM-PAO as the flow tracer are also exagger ated as discussed by Lassen et al (1988). vs. time (bottom).…”