Biomedical subjects

B R Zeeberg

Publications and source records attributed to B R Zeeberg.

At least 19 recordsLinked to original sources

PubMed2000

In vitro and in vivo m2 muscarinic subtype selectivity of some dibenzodiazepinones and pyridobenzodiazepinones.

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype receptors in cortical and hippocampal regions of the human brain. Emission tomographic study of the loss of m2 receptors in AD has been limited by the absence of available m2-selective radioligands, which can penetrate the blood-brain barrier. We now report on the in vitro and in vivo m2 muscarinic subtype selectivity of a series of dibenzodiazepinones and pyridobenzodiazepinones determined by competition studies against (R)-3-quinuclidinyl (S)-4-iodobenzilate ((R,S)-[125I]IQNB) or [3H]QNB. Of the compounds examined, three of the 5-[[4-[(4-dialkylamino)butyl]-1-piperidinyl]acetyl]-10, 11-dihydro-5-H-dibenzo[b,e][1,4]diazepin-11-ones (including DIBA) and three of the 11-[[4-[4-(dialkylamino)butyl]-1-phenyl]acetyl]-5, 11-dihydro-6H-pyrido [2,3-b][1,4]benzodiazepin-6-ones (including PBID) exhibited both high binding affinity for the m2 subtype (</=5 nM) and high m2/m1 selectivity (>/=10). In vivo rat brain dissection studies of the competition of PBID or DIBD against (R,S)[125I]IQNB or [3H]QNB exhibited a dose-dependent preferential decrease in the binding of the radiotracer in brain regions that are enriched in the m2 muscarinic subtype. In vivo rat brain autoradiographic studies of the competition of PBID, BIBN 99, or DIBD against (R,S)[125I]IQNB exhibited an insignificant effect of BIBN 99 and confirmed the effect of PBID and DIBD in decreasing the binding of (R,S)[125I]IQNB in brain regions that are enriched in the m2 muscarinic subtype. We conclude that PBID and DIBD are potentially useful parent compounds from which in vivo m2 selective derivatives may be prepared for potential use in positron emission tomographic (PET) study of the loss of m2 receptors in AD.

Alzheimer Disease↗

PubMed1999

Pharmacokinetic computer simulations of the relationship between in vivo and in vitro neuroreceptor subtype selectivity of radioligands.

Pharmacokinetic computer simulations reveal a discrepancy between the in vivo and in vitro neuroreceptor subtype selectivity of radioligands. For radioligands with an in vitro neuroreceptor subtype selectivity between 0.1 and 10.0, the in vivo neuroreceptor subtype selectivity appears to be constrained to be between 0.1 and 10.0, but, in general, is not equal to the in vitro selectivity. For example, if the in vitro selectivity is 1.0 (that is, the radioligand is nonselective in vitro) the in vivo selectivity may be thought of as a random variable having a significant nonzero probability for values as low as 0.1 or as high as 10.0, with a moderate peak at a value of 1.0. For a radioligand whose in vitro subtype selectivity is greater than 10.0, the in vivo selectivity is bounded above by the in vitro subtype selectivity, but may be several orders of magnitude lower than the in vitro subtype selectivity. Thus, in spite of the discrepancy between the in vivo and in vitro neuroreceptor subtype selectivity of radioligands, there are two useful inferences about the in vivo selectivity that might be drawn from knowledge of the in vitro selectivity: (1) If the in vitro selectivity is between 0.1 and 10.0, then, at best, the in vivo selectivity might be as high as 10.0. (2) If the in vitro selectivity is greater than 10.0, then, at best, the in vivo selectivity might be as high as the in vitro selectivity.

Animals↗

PubMed1998

In vivo competition studies of Z-(-,-)-[125I]IQNP against 3-quinuclidinyl 2-(5-bromothienyl)-2-thienylglycolate (BrQNT) demonstrating in vivo m2 muscarinic subtype selectivity for BrQNT.

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in cortical and hippocampal regions of the human brain. Until recently, emission tomographic study of the loss of m2 receptors in AD has been limited by the absence of available m2-selective radioligands that can penetrate the blood-brain barrier. We now demonstrate the in vivo m2 selectivity of an analog of (R)-QNB, 3-quinuclidinyl 2-(5-bromothienyl)-2-thienylglycolate (BrQNT), by dissection and autoradiographic studies of the in vivo inhibition of radioiodinated Z-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenyl-acetate (Z-(-,-)-[125I]IQNP) binding by unlabeled BrQNT in rat brain. In the absence of BrQNT, Z-(-,-)-[125I]IQNP labels brain regions containing muscarinic receptors, with an enhanced selectivity for the m2 subtype. In the presence of 60-180 nmol of co-injected racemic BrQNT, Z-(-,-)-[125I]IQNP labeling in those brain regions containing predominantly m2 subtype is reduced to background levels, while levels of radioactivity in areas not enriched in the m2 subtype do not significantly decrease. We conclude that BrQNT is m2-selective in vivo, and that [76Br]BrQNT, or a radiofluorinated analog, may be of potential use in positron emission tomographic (PET) study of the loss of m2 receptors in AD. In addition, a radioiodinated analog may be of potential use in single photon emission tomographic (SPECT) studies.

Alzheimer Disease↗

PubMed1997

In vivo autoradiography of radioiodinated (R)-3-quinuclidinyl (S)-4-iodobenzilate [(R, S)-IQNB] and (R)-3-quinuclidinyl (R)-4-iodobenzilate [(R,R)-IQNB]. Comparison of the radiolabelled products of a novel tributylstannyl precursor with those of the established triazene and exchange methods.

Radioiodinated (R,S)-IQNB and (R,R)-IQNB are prepared either from a triazene precursor or using an exchange reaction. In both cases the radiochemical yield is low. The product of the exchange reaction also suffers from having a fairly low specific activity. A new method for preparing radioiodinated (R,S)-IQNB and (R,R)-IQNB from a tributylstannyl precursor has recently been developed. This method is more convenient and much faster than the triazene and exchange methods, and it reliably results in a high radiochemical yield of a high specific activity product. In rat brain, the in vivo properties of the radioiodinated products of the tributylstannyl method are identical to those of the corresponding radioiodinated (R,S)-IQNB and (R,R)-IQNB prepared using the triazene and exchange methods. Dissection studies of selected brain regions show that at 3 h post injection (R,S)-[125I]IQNB prepared by all three methods have indistinguishable % dose g-1 values in all brain regions studied. Autoradiographic comparison of coronal slices through the anteroventral nucleus of the thalamus, through the hippocampus and through the pons at 2 h post injection shows that (R,S)-[125I]IQNB prepared by the triazene and tributylstannyl methods have indistinguishable patterns of binding.

Animals↗

PubMed1997

Correction of the stereochemical assignment of the benzilic acid center in (R)-(-)-3-quinuclidinyl (S)-(+)-4-iodobenzilate [(R,S)-4-IQNB].

Radioiodinated (R)-quinuclidinyl-4-iodobenzilate (4IQNB) is a high affinity muscarinic antagonist which has been utilized for in vitro and in vivo assays, and for SPECT imaging in humans. 4IQNB exists in four different diastereomeric forms, since there are two asymmetric centers at the quinuclidinyl and benzilic acid centers. Based upon our in vivo studies, we have determined that the absolute stereochemistry previously assigned to the benzilic center was incorrect for the diastereomer that had been previously referred to as '(R)-quinuclidinyl-(R)-4-iodobenzilate' [(R,R)-4IQNB]. The correct designation for this diastereomer is '(R)-quinuclidinyl-(S)-4-iodobenzilate' [(R,S)-4IQNB].

Animals↗

PubMed1997

In vivo autoradiographic competition studies of isomers of [125I]IQNP against QNB demonstrating in vivo m2 muscarinic subtype selectivity for QNB.

(R,S)-[125I]IQNB has been used extensively in in vivo studies in rats, and has been of utility in demonstrating the in vivo subtype selectivity of nonradioactive ligands in competition studies. Because of the implications for the study of Alzheimer's disease (AD), those ligands that demonstrate m2 selectivity are of particular interest. Radiolabelled Z- and E-(-,-)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (Z- and E-(-,-)-[125I]IQNP) are analogs of (R,S)-[125I]IQNB. Rat brain regional dissection studies and in vivo autoradiographic comparison of the time-courses of (R,S)-[125I]IQNB, Z-(-,-)-[125I]IQNP, and E-(-,-)-[125I]IQNP have indicated that Z- and E-(-,-)-[125I]IQNP, in general, are distributed similarly to (R,S)-[125I]IQNB. Z-(-,-)-[125I]IQNP binds to the muscarinic receptors in those brain regions enriched in the m2 subtype with approximately a two- to fivefold higher % dose/g compared with (R,S)-[125I]IQNB. Thus, as we show here autoradiographically, using QNB as the competing nonradioactive ligand in in vivo competition studies against Z-(-,-)-[125I]IQNP provides a sensitive and accurate probe for demonstrating the in vivo m2 selectivity of nonradioactive ligands.

Animals↗

PubMed1996

Autoradiographic evidence that 3-quinuclidinyl-4-fluorobenzilate (FQNB) displays in vivo selectivity for the m2 subtype.

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in cortical and hippocampal regions of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. We now demonstrate the in vivo m2 selectivity of a fluorine derivative of QNB (FQNB), by studying autoradiographically the in vivo inhibition of radioiodinated (R)-3-quinuclidinyl (S)-4-iodobenzilate ((R,S)-[125I]IQNB) binding by unlabeled FQNB. In the absence of FQNB, (R,S)-[125I]IQNB labels brain regions in proportion to the total muscarinic receptor concentration; in the presence of 30.0 nmol of racemic FQNB, (R,S)-[125I]IQNB labeling in those brain regions containing predominantly the m2 subtype is reduced to background levels. We conclude that FQNB is m2-selective in vivo and that [18F]FQNB or a closely related analogue may be of potential use in positron emission tomographic study of the loss of m2 receptors in AD.

Alzheimer Disease↗

PubMed1996

Specific binding component of the "inactive" stereoisomer (S,S)-[125I] IQNB to rat brain muscarinic receptors in vivo.

In vivo nonspecific binding can be estimated using the inactive stereoisomer of a receptor radioligand. However, the binding of the inactive stereoisomer may be partially specific. Specific binding of the inactive (S,S)-[125I]IQNB was estimated from the inhibition induced by a competing nonradioactive ligand. This technique differed from the usual approach, since it was used to study the inactive rather than the active stereoisomer. The results indicate that there is substantial specific binding for (S,S)-[125I]IQNB.

Animals↗

PubMed1996

Autoradiographic evidence that (R)-3-quinuclidinyl (S)-4-fluoromethylbenzilate ((R,S)-FMeQNB) displays in vivo selectivity for the muscarinic m2 subtype.

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in cortical and hippocampal regions of the human brain. Until recently, emission tomographic study of the loss of m2 receptors in AD has been limited by the absence of available m2-selective radioligands that can penetrate the blood-brain barrier. We now demonstrate the in vivo m2 selectivity of a fluorinated derivative of QNB, (R)-3-quinuclidinyl (S)-4-fluoromethylbenzilate ((R,S)-FMeQNB), by studying autoradiographically the in vivo inhibition of radioiodinated (R)-3-quinuclidinyl (S)-4-iodobenzilate ((R,S)-[125I]IQNB) binding by unlabelled (R,S)-FMeQNB. In the absence of (R,S)-FMeQNB, (R,S)-[125I]IQNB labels brain regions in proportion to the total muscarinic receptor concentration; in the presence of 75 nmol of (R,S)-FMeQNB, (R,S)-[125I]IQNB labelling in those brain regions containing predominantly m2 subtype is reduced to background levels. We conclude that (R,S)-FMeQNB is m2-selective in vivo, and that (R,S)-[18F]FMeQNB may be of potential use in positron emission tomographic (PET) study of the loss of m2 receptors in AD.

Animals↗

PubMed1996

In vivo autoradiographic and dissection evaluation of isomers of 125I-labeled 1-azabicyclo[2.2.2] oct-3-yl-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (IQNP).

(R,S)-[125I]IQNB has been used extensively in in vivo studies in rats and has been of utility in demonstrating the in vivo subtype selectivity of nonradioactive ligands in competition studies. Radiolabeled Z- and E-(-,-)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (Z- and E-[-,-]-[125I]IQNP) are analogs of (R,S)-[125I]IQNB. Preliminary rat brain regional dissection studies have indicated that Z- and E-(-,-)-[125I]IQNP, in general, are distributed similarly to (R,S)-[125I]IQNB. An important observation is that Z-(-,-)-[125I]IQNP binds to the muscarinic receptors in those brain regions enriched in the m2 subtype with approximately a two- to fivefold higher percent dose/g compared to (R,S)-[125I]IQNB. These observations are confirmed here by in vivo autoradiographic comparison of the time-courses of (R,S)-[125I]IQNB, Z-(-,-)-[125I]IQNP, and E-(-,-)-[125I]IQNP. Thus, in vivo competition studies against Z-(-,-)-[125I]IQNP would provide a potentially more sensitive and accurate probe for demonstrating the in vivo m2 selectivity of the nonradioactive ligands. In addition, Z-(-,-)-[123I]IQNP would potentially be useful for SPECT imaging of muscarinic receptor loss in neurodegenerative diseases.

Animals↗

PubMed1995

Characterization of in vivo brain muscarinic acetylcholine receptor subtype selectivity by competition studies against (R,S)-[125I]IQNB.

We have studied the in vivo rat brain muscarinic acetylcholine receptor (mAChR) m2 subtype selectivities of three quinuclidine derivatives: (R)-3-quinuclidinyl benzilate (QNB), E-(+,+)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (E-(+,+)-IQNP), and E-(+,-)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (E-(+,-)-IQNP), and two tricyclic ring compounds: 5-[[4-[4-(diisobutylamino)butyl]-1-phenyl]-10,11-dihydro-5H-dibenz o [b,e][1,4]diazepin-11-one [sequence: see text] (DIBD) and 11-[[4-[4-(diisobutylamino)butyl-1-phenyl]acetyl]-5,11-dihydro-6H- pyrido [2,3-b][1,4]benzodiazepin-6-one [sequence: see text] (PBID), by correlating the regional inhibition of (R,S)-[125I]IQNB with the regional composition of the m1-m4 subtypes. Subtle effects are demonstrated after reduction of the between-animal variability by normalization to corpus striatum. Substantial in vivo m2-selectivity is exhibited by QNB and DIBD, modest in vivo m2-selectivity is exhibited by E-(+,+)-IQNP, and little or no in vivo m2-selectivity is exhibited by PBID and E-(+,-)-IQNP. Surprisingly, the in vivo m2-selectivity is not correlated with the in vitro m2-selectivity. For example, QNB, which appears to be the most strongly in vivo m2-selective compound, exhibits negligible in vitro m2-selectivity. These examples indicate that a strategy which includes only preliminary in vitro screening may very well preclude the discovery of a novel compound which would prove useful in vivo.

Animals↗

PubMed1995

Autoradiographic evidence that QNB displays in vivo selectivity for the m2 subtype.

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in cortical and hippocampal regions of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. We have previously reported the results of in vivo dissection studies, using both carrier-free and low specific activity [3H]QNB, which show that [3H]QNB exhibits a substantial in vivo m2 selectivity. Because of the expense of the radioligand and the long exposure time required for the X-ray film, performing a large number of direct in vivo autoradiographic studies using [3H]QNB is precluded. Therefore, we now confirm these results autoradiographically by studying the in vivo inhibition of radio-iodinated (R)-3-quinuclidinyl (S)-4-iodobenzilate ((R,S)-[125I]IQNB) binding by unlabeled QNB. In the absence of QNB, (R,S)-[125I]IQNB labels brain regions in proportion to the total muscarinic receptor concentration; in the presence of 15 nmol QNB, (R,S,)-[125I]IQNB labeling in those brain regions containing predominantly m2 subtype is reduced to background levels. We conclude that QNB is m2-selective in vivo and that a suitably radiolabeled derivative of QNB, possibly labeled with 18F, may be of potential use in positron emission tomographic study of the loss of m2 receptors in AD.

Animals↗

PubMed1995

Autoradiographic evidence that quinuclidinyl 4-(bromophenyl)-2-thienylglycolate (QBPTG) displays in vivo selectivity for the muscarinic m2 subtype.

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in cortical and hippocampal regions of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. We now demonstrate the in vivo m2 selectivity of an analogue of QNB, 4-(bromophenyl)-2-thienylglycolate (QBPTG), by studying autoradiographically the in vivo inhibition of radioiodinated (R)-3-quinuclidinyl (S)-4-iodobenzilate ((R,S)-[125I]IQNB) binding by unlabeled QBPTG in rat brain. In the absence of QBPTG, (R,S)-[125I]IQNB labels brain regions in proportion to the total muscarinic receptor concentration; in the presence of 37.5 nmol of racemic QBPTG, (R,S)-[125I]IQNB labeling in those brain regions containing predominantly the m2 subtype is reduced to background levels. We conclude that QBPTG is m2-selective in vivo and that [76Br]QBPTG, or a radiofluorinated analogue, may be of potential use in positron emission tomographic study of the loss of m2 receptors in AD. In addition, a radioiodinated analogue may be of potential use in single photon emission tomographic studies.

Alzheimer Disease↗

PubMed1995

Comparison of the in vivo rat brain regional pharmacokinetics of [3H]QNB, (R,S)-[125I]-4IQNB, and (R,R)-[125I]-4IQNB binding to the muscarinic acetylcholine receptor in relationship to the regional subtype composition.

We have used the dissection of selected rat brain regions to compare the in vivo pharmacokinetics of [3H]QNB, (R,S)-[125I]-4IQNB, and (R,R)-[125I]-4IQNB binding to the muscarinic acetylcholine receptor (mAChR). [3H]IQNB is distributed in accordance with the m2 subtype concentration, (R,S)-[125I]-4IQNB is distributed in accordance with the total mAChR concentration, and (R,R)-[125I]-4IQNB is distributed in accordance with the m1/m4 subtype concentration. Although the cerebellum is relatively poor in mAChR (composed almost exclusively of the m2 subtype), the [3H]QNB concentration in the cerebellum is nearly equal to that in the other brain regions and is predominantly composed of specific binding. In contrast, the (R,S)-[125I]-4IQNB and (R,R)-[125I]-4IQNB concentrations in the cerebellum are relatively low and are predominantly or exclusively composed of nonspecific binding. These results dramatically demonstrate the in vivo m2 selectivity of [3H]QNB. All three radioligands exhibit large population standard deviations, with a substantial reduction of the between-animal variability resulting from normalization to each individual animal's corpus striatum value. Thus, the large population standard deviations arise from variability in radioligand delivery (variations in global cerebral blood flow, radioligand binding to serum proteins, loss of parent radioligand through conversion to metabolites, and blood-brain barrier transport.

Animals↗

PubMed1994

[3H]QNB displays in vivo selectivity for the m2 subtype.

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in the posterior parietal cortex of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. [3H](R)-3-quinuclidinylbenzilate ([3H]QNB) is commonly used for performing in vitro studies of the muscarinic acetylcholine receptor (mAChR), either with membrane homogenates or with autoradiographic slices, in which [3H]QNB is nonsubtype-selective. We report here the results of in vivo studies, using both carrier-free and low specific activity [3H]QNB, which show that [3H]QNB exhibits a substantial in vivo m2-selectivity. Previously reported in vivo (R)-3-quinuclidinyl (R)-4-iodobenzilate ((R,R)-[125I]IQNB) binding appears to be nonsubtype-selective. Apparently the bulky iodine substitution in the 4 position reduces the subtype selectivity of QNB. It is possible that a less bulky fluorine substitution might permit retention of the selectivity exhibited by QNB itself. We conclude that a suitably radiolabeled derivative of QNB, possibly labeled with 18F, may be of potential use in positron emission tomographic (PET) study of the loss of m2 receptors in AD.

Animals↗

PubMed1993

A novel muscarinic receptor ligand which penetrates the blood brain barrier and displays in vivo selectivity for the m2 subtype.

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in the posterior parietal cortex of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. In our efforts to prepare such a radioligand, we have used competition studies against currently existing muscarinic receptor radioligands to infer the in vitro and in vivo properties of a novel muscarinic receptor ligand, 5-[[4-[4-(diisobutylamino)butyl]-1-phenyl]acetyl]-10,11-dihydro-5H - -dibenzo [b,e][1,4]diazepin-11-one (DIBD). In vitro competition studies against [3H](R)-3-quinuclidinylbenzilate ([3H]QNB) and [3H]N-methylscopolamine ([3H]NMS), using membranes derived from transfected cells expressing only m1, m2, m3, or m4 receptor subtypes, indicate that DIBD is selective for m2/m4 over m1/m3. In vivo competition studies against (R,R)-[125I]IQNB indicate that DIBD crosses the blood brain barrier (BBB). The relationship of the regional percentage decrease in (R,R)-[125I]IQNB versus the percentage of each of the receptor subtypes indicates that DIBD competes more effectively in those brain regions which are known to be enriched in the m2, relative to the m1, m3, and m4, receptor subtype; however, analysis of the data using a mathematical model shows that caution is required when interpreting the in vivo results. We conclude that a suitably radiolabeled derivative of DIBD may be of potential use in emission tomographic study of changes in m2 receptors in the central nervous system.

Animals↗

PubMed1993

Evaluation of reconstruction algorithms in SPECT neuroimaging: I. Comparison of statistical noise in SPECT neuroimages with 'naive' and 'realistic' predictions.

In the presence of statistical noise, an iterative reconstruction algorithm (IRA) for the quantitative reconstruction of single-photon-emission computed tomographic (SPECT) brain images overcomes major limitations of applying the standard filtered back projection (FBP) reconstruction algorithm to projection data which have been degraded by convolution of the true radioactivity distribution with a finite-resolution distance-dependent detector response: (a) the non-uniformity within the grey (or white) matter voxels which results even though the true model is uniform within these voxels; (b) a significantly lower ratio of grey/white matter voxel values than in the true model; and (c) an inability to detect an altered radioactivity value within the grey (or white) matter voxels. It is normally expected that an algorithm which improves spatial resolution and quantitative accuracy might also increase the magnitude of the statistical noise in the reconstructed image. However, the noise properties in the IRA images are very similar to those in the FBP images. In fact, the noise magnitude in both the FBP and IRA images is only slightly greater than that computed by the 'naive prediction', which presumably is a lower limit to the amount of statistical noise in a reconstructed image. Thus, the IRA should provide the potential for quantitative SPECT imaging of normal physiological responses or diseases involving both the brain grey and white matter.

Algorithms↗

PubMed1993

Evaluation of reconstruction algorithms in SPECT neuroimaging: II. Computation of deterministic and statistical error components.

For the reconstruction of a series of computer simulations of statistically-independent noisy realizations of projection data, the total error of the ith reconstructed voxel in the rth realization, Er,i, is composed of the statistical error, Sr,i, and the (deterministic) inaccuracy in the presence of noise, Di+. Di+ is composed of the (deterministic) inaccuracy in the absence of noise, Di-, and the (deterministic) additional inaccuracy in the presence of noise, Di delta. E(Er,i), the theoretical expected value of Er,i, is given by E(Er,i) = E(Di+) + E(Sr,i). Similarly, E(Di+) = E(Di-) + E(Di delta). The corresponding theoretical variances are given by sigma 2(Er,i) = sigma 2(Di+)+2C(Di+, Sr,i)+ sigma 2(Sr,i) and sigma 2(Di+) = sigma 2(Di-)+2C(Di-, Di delta)+ sigma 2(Di delta), where C(.,.) is the covariance. We have utilized these relationships to evaluate three reconstruction algorithms: standard filtered back projection (FBP), an iterative reconstruction algorithm (IRA), and a version of the IRA which incorporates a linear transformation (TIRA). For simulated brain images in which the projection data (500,000 events detected) were degraded as the result of convolution of the true radioactivity distribution with a realistic distance-dependent detector response function, for FBP the major contribution to both E(Er,i) and sigma 2(Er,i) was Di-. For the IRA and TIRA, the major contributions to E(Er,i) were Di- and Di delta, and the major contribution to sigma 2(Er,i) was Sr,i, although in some cases Di delta was also a contributing factor. Furthermore, the errors due to sigma 2(Er,i) (that is, [sigma 2(Er,i)]0.5) were more severe than those due to E(Er,i). We conclude that, in contrast to FBP, the effects of statistical noise are an important limiting factor for the IRA and TIRA, and that the future development of tomographic devices with higher sensitivity would expand the quantitative potential of the IRA and TIRA.

Algorithms↗