Neuroimaging in Drug Discovery and Development: Paradigms for Accelerating New Drug Availability

2001 ◽  
Vol 14 (5) ◽  
pp. 407-415
Author(s):  
John T. Metz ◽  
Malcolm D. Cooper ◽  
Terry F. Brown ◽  
Leann H. Kinnunen ◽  
Declan J. Cooper
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Glucose Metabolism ◽  
Phase Ii ◽  
New Drugs ◽  
Central Effects ◽  
Drug Discovery And Development ◽  
Psychological Tasks ◽  
The Brain ◽  
Phase Iv

The process of discovering and developing new drugs is complicated. Neuroimaging methods can facilitate this process. An analysis of the conceptual bases and practical limitations of different neuroimaging modalities reveals that each technique can best address different kinds of questions. Radioligand studies are well suited to preclinical and Phase II questions when a compound is known or suspected to affect well-understood mechanisms; they are also useful in Phase IV to characterize effective agents. Cerebral blood flow studies can be extremely useful in evaluating the effects of a drug on psychological tasks (mostly in Phase IV). Glucose metabolism studies can answer the simplest questions about whether a compound affects the brain, where, and how much. Such studies are most useful in confirming central effects (preclinical and early clinical phases), in determining effective dose ranges (Phase II), and in comparing different drugs (Phase IV).

Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia

1996 ◽  
Vol 270 (5) ◽  
pp. E746-E751 ◽  
Author(s):  
S. G. Hasselbalch ◽  
P. L. Madsen ◽  
L. P. Hageman ◽  
K. S. Olsen ◽  
N. Justesen ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Glucose Metabolism ◽  
Carbohydrate Metabolism ◽  
Ketone Bodies ◽  
Regional Analysis ◽  
Oxygen Metabolism ◽  
Blood Concentrations ◽  
Positron Emission ◽  
The Brain

During starvation, brain energy metabolism in humans changes toward oxidation of ketone bodies. To investigate if this shift is directly coupled to circulating blood concentrations of ketone bodies, we measured global cerebral blood flow (CBF) and global cerebral carbohydrate metabolism with the Kety-Schmidt technique before and during intravenous infusion with ketone bodies. During acute hyperketonemia (mean beta-hydroxybutyrate blood concentration 2.16 mM), cerebral uptake of ketones increased from 1.11 to 5.60 mumol.100 g-1.min-1, counterbalanced by an equivalent reduction of the cerebral glucose metabolism from 25.8 to 17.2 mumol.100 g-1.min-1, with the net result being an unchanged cerebral uptake of carbohydrates. In accordance with this, global cerebral oxygen metabolism was not significantly altered (144 vs. 135 mumol.100 g-1.min-1). The unchanged global cerebral metabolic activity was accompanied by a 39% increase in CBF from 51.0 to 70.9 ml.100 g-1.min-1. Regional analysis of the glucose metabolism by positron emission tomography-[18F]fluoro-2-deoxy-D-glucose indicated that mesencephalon does not oxidize ketone bodies to the same extent as the rest of the brain. It was concluded that the immediate oxidation of ketone bodies induced a decrease in cerebral glucose uptake in spite of an adequate glucose supply to the brain. Furthermore, acute hyperketonemia caused a resetting of the coupling between CBF and metabolism that could not be explained by alterations in arterial CO2 tension or pH.

Vorläufige Ergebnisse von 99mTc-HMPAO-SPECT-Untersuchungen bei endogenen Psychosen

1989 ◽  
Vol 28 (03) ◽  
pp. 88-91
Author(s):  
J. Schröder ◽  
H. Henningsen ◽  
H. Sauer ◽  
P. Georgi ◽  
K.-R. Wilhelm
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Regional Cerebral Blood Flow ◽  
Regions Of Interest ◽  
Post Mortem ◽  
Regional Cerebral Blood ◽  
Hmpao Spect ◽  
Endogenous Psychoses ◽  
The Brain ◽  
99Mtc Hmpao

18 psychopharmacologically treated patients (7 schizophrenics, 5 schizoaffectives, 6 depressives) were studied using 99mTc-HMPAO-SPECT of the brain. The regional cerebral blood flow was measured in three transversal sections (infra-/supraventricular, ventricular) within 6 regions of interest (ROI) respectively (one frontal, one parietal and one occipital in each hemisphere). Corresponding ROIs of the same section in each hemisphere were compared. In the schizophrenics there was a significantly reduced perfusion in the left frontal region of the infraventricular and ventricular section (p < 0.02) compared with the data of the depressives. The schizoaffectives took an intermediate place. Since the patients were treated with psychopharmaca, the result must be interpreted cautiously. However, our findings seem to be in accordance with post-mortem-, CT- and PET-studies presented in the literature. Our results suggest that 99mTc-HMPAO-SPECT may be helpful in finding cerebral abnormalities in endogenous psychoses.

scholarly journals Examination of Potential Mechanisms in the Enhancement of Cerebral Blood Flow by Hypoglycemia and Pharmacological Doses of Deoxyglucose

1997 ◽  
Vol 17 (1) ◽  
pp. 54-63 ◽  
Author(s):  
Naoaki Horinaka ◽  
Nicole Artz ◽  
Jane Jehle ◽  
Shinichi Takahashi ◽  
Charles Kennedy ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Glucose Metabolism ◽  
Plasma Glucose ◽  
Plasma Lactate ◽  
Insulin Hypoglycemia ◽  
Glucose Levels ◽  
Arterial Blood ◽  
Arterial Plasma

Cerebral blood flow (CBF) rises when the glucose supply to the brain is limited by hypoglycemia or glucose metabolism is inhibited by pharmacological doses of 2-deoxyglucose (DG). The present studies in unanesthetized rats with insulin-induced hypoglycemia show that the increases in CBF, measured with the [14C]iodoantipyrine method, are relatively small until arterial plasma glucose levels fall to 2.5 to 3.0 m M, at which point CBF rises sharply. A direct effect of insulin on CBF was excluded; insulin administered under euglycemic conditions maintained by glucose injections had no effects on CBF. Insulin administration raised plasma lactate levels and decreased plasma K+ and HCO3– concentrations and arterial pH. These could not, however, be related to the increased CBF because insulin under euglycemic conditions had similar effects without affecting CBF; furthermore, the inhibition of brain glucose metabolism with pharmacological doses (200 mg/kg intravenously) of DG increased CBF, just like insulin hypoglycemia, without altering plasma lactate and K+ levels and arterial blood gas tensions and pH. Nitric oxide also does not appear to mediate the increases in CBF. Chronic blockade of nitric oxide synthase activity by twice daily i.p. injections of NG-nitro-L-arginine methyl ester for 4 days or acutely by a single i.v. injection raised arterial blood pressure and lowered CBF in normoglycemic, hypoglycemic, and DG-treated rats but did not significantly reduce the increases in CBF due to insulin-induced hypoglycemia (arterial plasma glucose levels, 2.5-3 m M) or pharmacological doses of deoxyglucose.

Effects of Cytoflavin and Neuronol on Morphological Changes in the Brain and Survival of Rats with Ischemic Disturbances in Cerebral Blood Flow

2004 ◽  
Vol 137 (4) ◽  
pp. 411-414 ◽  
Author(s):  
V. V. Bulon ◽  
I. B. Krylova ◽  
N. R. Evdokimova ◽  
A. L. Kovalenko ◽  
L. E. Alekseeva ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Morphological Changes ◽  
The Brain

scholarly journals Use of 19F NMR Spectroscopy for Measurement of Cerebral Blood Flow: A Comparative Study Using Microspheres

1989 ◽  
Vol 9 (6) ◽  
pp. 886-891 ◽  
Author(s):  
David Barranco ◽  
Leslie N. Sutton ◽  
Sandra Florin ◽  
Joel Greenberg ◽  
Teresa Sinnwell ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Arterial Blood ◽  
Radioactive Microsphere ◽  
Low Concentrations ◽  
Cat Brain ◽  
Nmr Techniques ◽  
High Concentrations ◽  
Washout Curves ◽  
The Brain

19F NMR was used to determine washout curves of an inert, diffusible gas (CHF3) from the cat brain. The cerebral blood flow was estimated from a bi- or tri-phasic fit to the deconvoluted wash-out curve, using the Kety-Schmidt approach. Cerebral blood flow values determined by 19F NMR show the expected responsiveness to alterations in Paco2, but are approximately 28% lower than cerebral blood flow values determined simultaneously by radioactive microsphere techniques. High concentrations of CHF3 have little effect on intracranial pressure, mean arterial blood pressure or Paco2, but cause small changes in the blood flow to certain regions of the brain. We conclude that 19F NMR techniques utilizing low concentrations of CHF3 have potential for the noninvasive measurement of cerebral blood flow.

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