European Journal of Nuclear Medicine

, Volume 21, Issue 3, pp 196–202 | Cite as

Dual-isotope autoradiographic measurement of regional blood flow and benzodiazepine receptor availability following unilateral middle cerebral artery occlusion

  • Mohammed S. Al-Tikriti
  • Holley M. Dey
  • Sami S. Zoghbi
  • Ronald M. Baldwin
  • Yolanda Zea-Ponce
  • Robert B. Innis
Original Articles
Received:
Revised:

Abstract

Single-photon emission tomography (SPET) imaging in patients with complex partial epilepsy has shown that the seizure focus is characterized by both decreased interictal blood flow and decreased uptake of the benzodiazepine (BZ) receptor tracer iodine-123 iomazenil. The purpose of this study was to examine the confounding effect of decreased flow on iomazenil uptake. The left middle cerebral artery of four rats was occluded, and the animals were simultaneously injected with 25 μCi of iodine-125 iomazenil and 500 μCi of the blood flow tracer [123I]iofetamine (N-isopropyl-p-iodoamphetamine). All rats, including two sham, were sacrificed 1 h after injection, a time when uptake of both agents is nearly maximal. Control experiments showed that arterial occlusion for 1 h did not affect the total number of BZ binding sites. Using a dual autoradiographic technique, the uptake of both [123I]iofetamine and [125I]iomazenil was measured in more than 200 regions showing variable levels of reduced flow and expressed as a percentage of the contralateral homotypic area. The straight line fit of % [125I]iomazenil (y axis) versus % [123I]iofetamine (x axis) in all 200 regions had a slope of 0.74. Insofar as the rat is an accurate model of human subjects with epilepsy, these studies suggest that decreased flow to the epileptogenic focus will linearly exacerbate the decrease in uptake secondary to neuropathologic loss of BZ receptors. Thus, for localization of seizure focus, a single SPET image of [123I]iomazenil in an epileptic patient may have greater sensitivity than a comparable blood flow image, because the former is enhanced by both decreased flow and a loss of BZ receptors.

Key words

Benzodiazepine receptor Iodine-123 isopropyl-p-iodoamphetamine Iomazenil Ischemia Autoradiography 
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Savic I, Roland P, Sedvall G, Persson A, Pauli S, Widen L. In vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci. Lancet 1988;11:863–866.Google Scholar
  2. 2.
    Duncan S, Gillen G, Adams FG, Dunce R, Brodie MJ. Interictal HM-PAO SPELT: a routine investigation in patients with medically intractable complex partial seizures? Epilepsy Res 1992;13:83–87.Google Scholar
  3. 3.
    Duncan S, Gillen GJ, Brodie MJ. Lack of effect of concomitant clobazam on interictal 123I-iomazenil SPECT. Epilepsy Res 1993;15:61–66.Google Scholar
  4. 4.
    Schubiger PA, Hasler PH, Beer-Wohlfahrt H, Bekier A, Oettli R, Cordes M, Ferstl F, Deisenhammer E, De Roo M, Moser E, Nitzsche E, Podreka I, Riccabona G, Bangerl I, Schober O, Bartenstein P, Van Rijk P, Van Isselt JW, Van Royen EA, Verhoeff NPLG, Haldemann R, Von Schulthess GK. Evaluation of a multi-center study with iomazenil — a benzodiazepine receptor ligand. Nucl Med Commun 1991;12:569–582.Google Scholar
  5. 5.
    Woods SW, Seibyl JP, Goddard AW, Dey HM, Zoghbi SS, Germine M, Baldwin RM, Hoffer PB, Charney DS, Heninger GR, Innis RB. Dynamic SPECT imaging of the benzodiazepine receptor in healthy human subjects with [123I]Ro 16–0154 and SPECT. Psych Res Neuroimaging 1992;45:67–77.Google Scholar
  6. 6.
    Beer H-F, Blauenstein PA, Hasler PH, Delaloye B, Riccabona G, Bangerl I, Hunkeler W, Bonetti EP, Pieri L, Richards JG, Schubinger PA. In vitro and in vivo evaluation of iodine-123 Ro 16–0154: a new imaging agent for SPECT investigations of benzodiazepine receptors. J Nucl Med 1990;31:1007–1014.Google Scholar
  7. 7.
    Kung HF, Billings JJ, Guo Y-Z, Mach RH. Comparison of in vivo D2 dopamine receptor binding of IBZM and NMSP in rat brain. Nucl Med Biol 1988;15:203–208.Google Scholar
  8. 8.
    Lear JL. Quantitative multple tracer autoradiography: considerations in optimizing precision and accuracy. J Cereb Blood Flow Metab 1988;8:443–448.Google Scholar
  9. 9.
    Winchell HS, Horst WD, Braun L, Oldendorf WH, Hatmer R, Parker H. N-Isopropyl-[123I]-p-iodoamphetamine: single-pass brain uptake and washout; binding to synaptosomes; and localization in dog and monkey brain. J Nucl Med 1980;21:947–952.Google Scholar
  10. 10.
    Kuhl DE, Barrio JR, Huang S-C, Selin C, Ackermann RF, Lear JL, Wu JL, Lin TH, Phelps ME. Quantifying local cerebral blood flow by N-isopropyl-p-[123I]-iodoamphetamine (IMP) tomography. J Nucl Med 1982;23:196–203.Google Scholar
  11. 11.
    Zoghbi SS, Baldwin RM, Seibyl JP, Al-Tikriti MS, Zea-Ponce Y, Laruelle M,. Sybirska EH, Woods SW, Goddard AW, Charney DS, Smith EO, Hoffer PB, Innis RB. Pharmacokinetics of the SPECT benzodiazepine receptor radioligand [123I]iomazenil in human and nonhuman primates: Int J Rad Appl Instrum [B] 1992;19:881–888.Google Scholar
  12. 12.
    Zea-Ponce Y, Baldwin R, Zoghbi SS, Innis RB. Formation of 1-[123I]iodobutane in iododestannylation with [123I]iomazenil compared to IBF, epidepride, and β-CIT, and its relationship to the mechanism of the reaction Int J Rad Appl Instrunz [A] 1994;45:63–68.Google Scholar
  13. 13.
    McBride BJ, Baldwin RM, Kerr JM, Wu J-L. A simple method for the preparation of 123I and 125I labeled iodobenzodiazepines. Int J Rad Appl Instrum [A] 1991;42:173–175.Google Scholar
  14. 14.
    Tamura A, Graham DI, McCulloch J, Teasdale GM. Focal cerebral ischaemia in the rat. I. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab 1981;1:53–60.Google Scholar
  15. 15.
    Paxinos G, Watson C. The rat brain in stereotaxic coordinates. Sydney: Academic Press, 1986.Google Scholar
  16. 16.
    Johnson EW, Sybirska E, Al-Tikriti M, Innis RB. Calibration of [123I]iodine labeled tissue standards autoradiographic analysis. Int J Rod Appl Instrum [A] 1991;42:1199–1201.Google Scholar
  17. 17.
    Artymyshyn R, Smith A, Wolfe BB. The use of 3H standards in 125I autoradiography. J Neurosci Methods 1990;32:185–192.Google Scholar
  18. 18.
    Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ. A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 1984;15:217–227.Google Scholar
  19. 19.
    Whitehouse PJ, Lynch D, Kuhar MJ. Effects of postmortem delay and temperature on neurotransmitter receptor binding in a rat model of the human autopsy process. J Neurochem 1984;43:553–559.Google Scholar
  20. 20.
    Beer H-F, Blauenstein PA, Hasler PH, Schubiger PA, Hunkeler W, Bibettu EP, Pieri L, Richards JG. Iomazenil: pharmacological and animal data. In: Schubiger PA, Hasler PH, eds. Iomazenil and other brain receptor tracers for SPECT. Basel: Editiones Roche, 1990:10–29.Google Scholar
  21. 21.
    Innis RB, Al-Tiktiti MS, Zoghbi SS, Baldwin RM, Sybirska EH, Laruelle MA, Malison RT, Seibyl JP, Zimmermann RC, Johnson EW, Smith EO, Charney DS, Hettinger GR, Woods SW, Hoffer PB. SPECT imaging of the benzodiazepine receptor: feasibility of in vivo potency measurements from stepwise displacement curves.J Nucl Med 1991; 32:1654–1661.Google Scholar
  22. 22.
    Johnson EW, de Lanerolle NC, Kim JH, Sundaresan S, Spencer DD, Mattson RH, Zoghbi SS, Baldwin RM, Hoffer PB, Seibyl JP, Innis RB. “Central” and “peripheral” benzodiazepine receptors: opposite changes in human epileptogenic tissue. Neurology 1992;42:811–815.Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Mohammed S. Al-Tikriti
    • 1
  • Holley M. Dey
    • 1
  • Sami S. Zoghbi
    • 1
  • Ronald M. Baldwin
    • 1
  • Yolanda Zea-Ponce
    • 1
  • Robert B. Innis
    • 1
  1. 1.Yale University School of Medicine/VA Medical CenterWest HavenUSA

Personalised recommendations