Biomedical subjects

P B Hoffer

Publications and source records attributed to P B Hoffer.

At least 19 recordsLinked to original sources

PubMed2000

[123I]IPCIT and [123I]beta-CIT as SPECT tracers for the dopamine transporter: a comparative analysis in nonhuman primates.

[123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]-CIT) and its isopropylester analog [123I]PCIT, both of which are phenyltropane derivatives of cocaine with high affinity for the dopamine (DA) transporter, were compared using single photon emission computed tomography in nonhuman primates. Although IPCIT is significantly more selective for the DA transporter than beta-CIT, striatal distribution volumes of specifically bound tracer were similar for both tracers. Compartmental modeling results were compared with a simple peak equilibrium method used previously by this group. The peak equilibrium method is shown to overestimate striatal distribution volumes, primarily due to a difference in the calculated time of peak specific uptake.

Animals↗

PubMed1998

Absence of an apolipoprotein E epsilon4 allele is associated with increased parietal regional cerebral blood flow asymmetry in Alzheimer disease.

BACKGROUND: The apolipoprotein E (Apo E) epsilon4 allele has been associated with parietal metabolic abnormalities and asymmetries in asymptomatic subjects at risk for Alzheimer disease (AD). However, previous research has shown minimal effect of the epsilon4 allele on regional cerebral blood flow (rCBF) and metabolism in patients with probable AD. OBJECTIVE: To determine whether the Apo E epsilon4 allele is associated with parietal rCBF abnormalities and asymmetries in patients with probable AD. PATIENTS AND METHODS: Thirty patients with AD with the epsilon4 allele (epsilon4+ AD), 22 patients with AD without the epsilon4 allele (epsilon4- AD), and 14 healthy control subjects underwent single-photon emission computed tomography (SPECT) scanning with 740 MBq technetium Tc 99m hexamethylpropyleneamine oxime. Ratios of parietal-unaffected regions and a left-right parietal asymmetry index were compared between both patient groups. RESULTS: The group with epsilon4- AD was younger (P = .005, Student t test) and had an earlier age of onset (P = .005) than the group with epsilon4+ AD. Analysis of covariance revealed no significant difference in the parietal rCBF ratio, controlling for age of onset and Mini-Mental State Examination score (F(1,48) = 0.06; P = .81). However, contrary to hypothesis, significantly greater parietal rCBF asymmetry was seen in patients with epsilon4- AD (mean +/- SD, 9.7% +/- 5.5%) than those with epsilon4+ AD (6.3% +/- 4.7%; F(1,50) = 5.89; P = .02; analysis of variance). When number of epsilon4 allele copies was considered, this effect appeared to accrue primarily from a difference between patients with 0 and with 2 epsilon4 allele copies. An exploratory analysis of multiple cortical structures suggested that this asymmetry extended to additional regions (superior temporal) and to combined association cortex. CONCLUSIONS: Greater parietal rCBF asymmetry is involved in epsilon4- AD than in epsilon4+ AD. Lack of the epsilon4 allele may be associated with other (as yet undiscovered) genetic or environmental risk factors, which confer greater neuropathological asymmetry.

Age of Onset↗

PubMed1997

Microdialysis and SPECT measurements of amphetamine-induced dopamine release in nonhuman primates.

The competition between endogenous transmitters and radiolabeled ligands for in vivo binding to neuroreceptors might provide a method to measure endogenous transmitter release in the living human brain with noninvasive techniques such as positron emission tomography (PET) or single photon emission computerized tomography (SPECT). In this study, we validated the measure of amphetamine-induced dopamine release with SPECT in nonhuman primates. Microdialysis experiments were conducted to establish the dose-response curve of amphetamine-induced dopamine release and to document how pretreatment with the dopamine depleter alpha-methyl-para-tyrosine (alpha MPT) affects this response. SPECT experiments were performed with two iodinated benzamides, [123I]IBZM and [123I]IBF, under sustained equilibrium condition. Both radio-tracers are specific D2 antagonists, but the affinity of [123I]IBZM (KD-0.4 nM) is lower than that of [123I]IBF (KD 0.1 nM). With both tracers, we observed a prolonged reduction in binding to D2 receptors following amphetamine injection. [123I]IBZM binding to D2 receptors was more affected than [123I]IBF by high doses of amphetamine, indicating that a lower affinity increases the vulnerability of a tracer to endogenous competition. With [123I]IBZM, we observed an excellent correlation between reduction of D2 receptor binding measured with SPECT and peak dopamine release measured with microdialysis after various doses of amphetamine. Pretreatment with alpha MPT significantly reduced the effect of amphetamine on [123I]IBZM binding to D2 receptors, confirming that this effect was mediated by intrasynaptic dopamine release. Together, these results validate the use of this SPECT paradigm as a noninvasive measurement of intrasynaptic dopamine release in the living brain.

Amphetamine↗

PubMed1997

The acetylcholine releaser linopirdine increases parietal regional cerebral blood flow in Alzheimer's disease.

Centrally acting cholinergic drugs have been reported to increase regional cerebral blood flow (rCBF) as measured by single photon emission computed tomography (SPECT) in brain regions affected by Alzheimer's disease (AD). We studied the effects of the acetylcholine releaser linopirdine (LPD) on SPECT rCBF in patients with probable AD. Twenty-four AD patients (12 M, 12 F; mean age +/- SD = 68.9 +/- 8.2 years) and 13 healthy controls (8 M, 5 F; 68.4 +/- 8.0 years) participated. AD patients were scanned with 20 mCi of Tc99m-ECD at baseline and following 4 weeks of treatment with LPD 40 mg TID (n = 15) or placebo TID (n = 9) in a double-blind trial. Healthy subjects were scanned for comparison with baseline AD scans. Cortical/cerebellar rCBF ratios were derived for nine cortical structures. The combined parietal association cortex showed a 20.6% reduction in patients relative to controls. Patients treated with LPD showed an increase in parietal rCBF of 4.1 +/- 5.8%; whereas those treated with placebo showed a decrease of -2.0 +/- 7.4% (F = 5.13; df = 1, 22; P = 0.03). These data support the conclusion that rCBF abnormalities in AD are, in part, truly "functional" and can be selectively altered with pharmacological interventions. The parietal activation seen with LPD and other cholinergic AD drug therapies suggests the importance of measuring parietal lobe neuropsychological function in the course of evaluating these drugs.

Acetylcholine↗

PubMed1997

Test/retest reproducibility of iodine-123-betaCIT SPECT brain measurement of dopamine transporters in Parkinson's patients.

UNLABELLED: Iodine-123-beta-CIT has been used as a probe of dopamine transporters in Parkinson's disease patients using SPECT. We studied the test/retest reproducibility of SPECT measures in Parkinson's disease patients and healthy controls obtained after injection of [123I])beta-CIT in part to assess the utility of this tracer for longitudinal evaluation of striatal dopamine transporters as a marker of disease progression. METHODS: Seven Parkinson's disease patients and seven healthy control subjects participated in two [123I]beta-CIT SPECT scans separated by 7-21 days. Subjects were imaged at 24 hr post injection of 360 MBq (9.7 mCi) of [123I]beta-CIT. Two outcome measures were evaluated; 1) the ratio of specific striatal (activity associated with DA transporter binding) to nondisplaceable uptake, also designated V3," and 2) the total specific striatal uptake (%SSU) expressed as a percentage of injected radiotracer dose. For both measures, test/retest variability was calculated as the absolute difference of test minus retest divided by the mean of test/retest and expressed as a percent. In addition, the reproducibility of left and right striatal asymmetry and putamen:caudate ratios were determined. RESULTS: The two outcome measures demonstrated excellent test/retest reproducibility for both the Parkinson's disease and healthy subject groups with variability of striatal V3" = 16.8 +/- 13.3% and percent striatal uptake = 6.8 +/- 3.4% for Parkinson's disease patients and V3" = 12.8 +/- 8.9% and %SSU = 7.0 +/- 3.9% for control subjects. There were no statistically significant differences in test/retest variability between control subjects and Parkinson's disease patients for either outcome measure. The reproducibility of left/right asymmetry indices and putamen-to-caudate ratios showed no patient versus control subject differences. The asymmetry index had greater test/retest variability than the other outcome measures. CONCLUSION: These data suggest that SPECT imaging performed at 24 hr postinjection of [123I]beta-CIT permits calculation of reliable and reproducible measures of dopamine transporters in both Parkinson's disease patients and control subjects and supports the feasibility of using [123I]beta-CIT in the evaluation of disease progression in Parkinson's disease.

Adult↗

PubMed1996

Human biodistribution and dosimetry of the SPECT D2 dopamine receptor radioligand [123I]IBF.

The research discussed in this article aimed to characterize better the biodistribution, excretion and radiation dosimetry of the single photon emission computed tomography (SPECT) D2 Dopamine receptor radioligand [123I]IBF. Following administration of 111 +/- 12 MBq [123I]IBF, seven healthy human subjects were scanned serially with a whole body imager over a 48-h period. Transmission images were obtained with a scanning line source for attenuation correction of the emission images. Urine was collected for 48 h to measure the fraction of activity voided by the renal system. Radiation absorbed dose estimates were performed using biokinetic modeling and the Medical Internal Radiation Dose (MIRD) schema. Highest absorbed doses were to the kidney (0.13 +/- 0.02 mGy/MBq) and urinary bladder wall (0.11 +/- 0.01 mGy/MBq). The effective dose equivalent was 0.041 +/- 0.005 mSv/MBq. Peak brain uptake represented 8% of the injected activity. Rapid urinary excretion minimized the absorbed dose to most tissues. The mean cumulative urinary excretion fraction was 69%. Thus [123I]IBF is a promising SPECT agent for imaging the D2 dopamine receptor in humans with high brain uptake and favorable dosimetry.

Adult↗

PubMed1996

[123I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson's disease.

We have used in vivo single-photon emission computed tomography (SPECT) of the dopamine transporter with 2 beta-carboxymethoxy-3 beta-(4-iodophenyl)tropane ([123I] beta-CIT) to investigate striatal dopamine transporter loss in patients with early Parkinson's disease (PD). Striatal uptake of ([123I] beta-CIT was compared in eight early-PD patients with exclusively hemi-parkinsonism and eight age- and sex-matched healthy subjects. [123I] beta-CIT striatal uptake was reduced by approximately 53% contralateral and by 38% ipsilateral to the clinically symptomatic side in the hemi-PD patients, compared with the mean striatal uptake in age- and sex-matched healthy subjects. The relative reduction in [123I] beta-CIT uptake in the hemi-PD patients was greater in the putamen than in the caudate. These data demonstrate that SPECT imaging of the dopamine transporter with [123I] beta-CIT can identify patients with PD at the onset of motor symptoms and suggest that this technique also may be useful in identifying individuals with developing dopaminergic pathology before onset of motor symptoms.

Adult↗

PubMed1996

Continuous intravenous infusion of iodine-123-IBZM for SPECT determination of human brain dopamine receptor occupancy by antipsychotic agent RWJ-37796.

UNLABELLED: PET has shown that dose-dependent in vivo occupancy of dopamine receptors by antipsychotic drugs is associated with clinical response to antipsychotic agents and the production of extrapyramidal side effects. We studied the feasibility of administering [123I]IBZM as a bolus plus continuous infusion over 8 hr to achieve unchanging regional brain activity levels, and the application of [123I]IBZM continuous infusion to examine the effects of the antipsychotic agent RWJ-37796, on striatal activity in humans. METHODS: Five healthy male subjects received a bolus of [123I]IBZM followed by a continuous infusion at a bolus (mCi):infusion (mCi/hr) ratio of 6:1. Serial SPECT images were obtained every 2-3 min for a total of 8 hr with a 1-2 hr break in the scanning session. Serial venous blood samples were obtained every 30 min for the duration of the study. All five subjects achieved unchanging plasma [123I]IBZM and striatal brain-activity levels over the 300-420 min postinitiation of tracer infusion. Two subjects achieved flat brain time-activity curves later than the others, suggesting the bolus-to-infusion ratio was slightly high. An additional six healthy male subjects received a similar bolus plus constant infusion of [123I]IBZM. RWJ-37796 (0.04 mg/kg) was administered intravenously 157 +/- 13.7 min after the initiation of [123I]IBZM infusion. Serial SPECT brain images, serum prolactin and extrapyramidal side effect ratings were obtained for an additional 330 min. RESULTS: All six subjects demonstrated rapid and marked reduction of striatal activity following RWJ-37796 without return of striatal activity to baseline levels over the 5.5 hr of continued [123I]IBZM administration. Estimated receptor occupancy by RWJ-37796 was 57% +/- 5% (range 47%-67%). Prolactin was only transiently increased in all subjects by 1054% +/- 1084% over baseline. One subject experienced moderate extrapyramidal symptoms (akasthisia) during RWJ-37796 injection. CONCLUSION: SPECT imaging during continuous [123I]IBZM infusion provides a powerful within-scan method for determining both temporal binding characteristics and receptor occupancy of striatal dopamine receptors by antipsychotic agents.

Adult↗

PubMed1996

Reproducibility of iodine-123-beta-CIT SPECT brain measurement of dopamine transporters.

UNLABELLED: Iodine-123-beta-CIT has been used as a probe of monoamine transporters in human and nonhuman primates utilizing SPECT. To assess the utility of this tracer for measurement of striatal dopamine (DA) transporters in human disease, we studied the test/retest variability and reliability of SPECT measures obtained after bolus injection of [123I]beta-CIT 0-7 hr (Day 1) and 18-24 hr (Day 2) after administration. METHODS: For the Day 2 study, seven healthy humans (4 men, 3 women; aged 19-74 yr) participated in two [123I]beta-CIT SPECT scans separated by 7-14 days. Subjects were imaged at 18, 21 and 24 hr postinjection of 370 MBq (10 mCi) [123I]beta-CIT. Two outcome measures were evaluated: (a) the ratio of specific striatal (activity associated with DA transporter binding) to nondisplaceable uptake, also designated V"3 and (b) the total, specific striatal uptake (%SSU) expressed as a percentage of injected radiotracer dose. Test/retest variability associated with V"3 and total specific striatal uptakes were compared for scans acquired at 18, 21 and 24 hr with 24 hr only postinjection scans. For the Day 1 study, three of the subjects participated in two kinetic studies of [123I]beta-CIT uptake. A three-compartment model was used for determination of konBmax and binding potential (BP = Bmax/Kd) and the reproducibility of the measures assessed. RESULTS: In the Day 2 study, both outcome measures demonstrated excellent test/retest reproducibility with variability of V"3 = 6.8 +/- 6.8% and percent striatal uptake = 6.6 +/- 4.3% using data acquired from all time points. There were no significant differences in variability for the two outcome measures obtained. The intraclass correlation coefficient rho was 0.96 and 0.98 for V"3 and %SSU, respectively. Considering the 24 hr postinjection scans only, there was a nonsignificant trend toward lower test/retest variability for %SSU compared to V"3 (6.6 +/- 4.2% and 12.8 +/- 9.0%, respectively). The test/retest variability for the Day 1 kinetic modeling data showed marked differences depending on the fitting strategy and assumptions about the reversibility of [123I]beta-CIT in striatum. Using a model that assumed a low, fixed value for reversible striatal binding (k4) produced low variability (12 +/- 9%). CONCLUSION: These data suggest that SPECT imaging performed at either 0-7 hr or 18-24 hr after [123I]beta-CIT injection permits calculation of reliable and reproducible measures of dopamine transporters and supports the feasibility of using [123I]beta-CIT in serial evaluation of human neuropsychiatric disease.

Adult↗

PubMed1996

Comparison of technetium-99m-HMPAO and technetium-99m-ECD cerebral SPECT images in Alzheimer's disease.

UNLABELLED: SPECT has shown increasing promise as a diagnostic tool in Alzheimer's disease (AD). Recently, a new SPECT brain perfusion agent, 99mTc-ethyl cysteinate dimer (99mTc-ECD) has emerged with purported advantages in image quality over the established tracer, 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO). This research aimed to compare cerebral images for 99mTc-HMPAO and 99mTc-ECD in discriminating patients with AD from control subjects. METHODS: Twenty-four AD patients (mean age +/- s.d. = 68.9 +/- 8.2 yr) and 13 healthy subjects (68.4 +/- 8.0 yr) were scanned sequentially with 20 mCi of each tracer using the CERASPECT system within 1 mo. Scanning began on average 11.5 +/- 2.8 min after 99mTc-HMPAO injection and 41.8 +/- 10.1 min after 99mTc-ECD. A ratio, R, was derived of count densities in "typically affected" brain structures (parietal and temporal association cortices) to "unaffected" structures (cerebellum, basal ganglia, thalamus, occipital cortex, and sensorimotor cortex). RESULTS: Analysis of variance revealed significant interaction between diagnostic group and radiopharmaceutical (F = 4.71; df = 1.35; p = 0.04), with 99mTc-ECD demonstrating better separation of R values between AD patients and control subjects than 99mTc-HMPAO. Receiver operating characteristic (ROC) analysis, revealed no significant difference in the ability of the two tracers to correctly classify AD patients and control subjects. Both tracers showed high diagnostic accuracy (99mTc-ECD: sensitivity = 100%, specificity = 92%; 99mTc-HMPAO: sensitivity = 100%, specificity = 85%). CONCLUSION: Technetium-99m-ECD shows greater contrast than 99mTc-HMPAO between affected and unaffected brain structures in AD when patients are compared to age-matched control subjects. Both tracers perform equally well in correctly classifying patients and control subjects.

Aged↗

PubMed1996

SPECT imaging of dopamine transporters in human brain with iodine-123-fluoroalkyl analogs of beta-CIT.

Iodine-123-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane (beta-CIT) is a useful SPECT tracer for imaging the dopamine transporter. Its slow kinetics, however, necessitate imaging on the day after the injection. Two N-omega-fluoroalkyl analogs of beta-CIT, the fluoropropyl and fluoroethyl compounds (beta-CIT-FP and beta-CIT-FE, respectively), characterized by faster kinetics in baboons, were tested in humans as potential tracers for the dopamine transporter. Four healthy volunteers were injected with [123I]-beta-CIT-FP and another four were injected with [123I]beta-CIT-FE. SPECT data were acquired for 1149 +/- 590 min and 240 +/- 30 min, respectively. Both tracers demonstrated high brain uptake (6.37% +/- 0.37% and 7.8% +/- 1.5% of the injected dose, respectively). Activity concentrated with time in the striatal area, reaching a peak within 30 min, with little or no washout for [123I]beta-CIT-FP and a faster washout for [123I]beta-CIT-FE (14.7% +/- 6.9%). Occipital and midbrain activity showed similar patterns, displaying a peak within 15 min and rapid washout, followed by stable levels at approximately 100 min for both tracers. The ratio of peak specific striatal-to-peak specific midbrain activity was 9.1 +/- 1.8 for [123I]beta-CIT-FP and 7.7 +/- 0.7 for [123I]beta-CIT-FE, showing high in vivo selectivity for the dopamine transporter. These preliminary results suggest that both compounds could be used as SPECT (labeled with 123I) or PET (labeled with 18F) radiotracers to image the dopamine transporters in the living human brain.

Adult↗

PubMed1995

Psychiatric status after human fetal mesencephalic tissue transplantation in Parkinson's disease.

This report describes the prospective and systematic psychiatric assessment of nine patients who received transplantation of human fetal mesencephalic tissue into the caudate nucleus for treatment of Parkinson's disease. Unlike adrenal medullary transplantation, which often causes psychosis or delirium, this procedure appeared to have few perioperative sequelae. On longer-term follow-up, there was some statistical evidence of deterioration in psychiatric status, as manifested primarily in depressive and nonspecific emotional and behavioral symptoms. This group effect was partly attributable to the occurrence of discrete episodes of illness (major depression and panic disorder with agoraphobia) in some patients, but it was unclear whether such episodes occurred more often than would ordinarily be expected in Parkinson's disease. Differences in the neurobiological effects of fetal mesencephalic and adrenal medullary grafts may account for differences in the psychiatric sequelae of patients receiving these procedures.

Adult↗

PubMed1995

Comparison of [123I]beta-CIT and [123I]IPCIT as single-photon emission tomography radiotracers for the dopamine transporter in nonhuman primates.

Single-photon emission tomographic (SPET) imaging with the radiotracer [123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT) has been reported to be a useful in vivo measure of dopamine (DA) transporters. However, in addition to its high DA transporter affinity, beta-CIT also binds with high affinity to serotonin (5-HT) transporters. 2 beta-Carboisopropoxy-3 beta-(4-iodophenyl)tropane (IPCIT) has been demonstrated by in vitro studies to have higher selectivity for the DA transporter. We compared [123I]beta-CIT and [123I]IPCIT SPET imaging and plasma metabolite analyses in baboons to evaluate the potential advantages of [123I]IPCIT for quantitative in vivo measurements of DA transporter densities. Both tracers had low levels (2% of total plasma 123I activity) of lipophilic radiolabeled metabolites at 420 min. [123I]IPCIT had significantly higher binding to plasma proteins. The average percent free (nonprotein bound) [123I]beta-CIT and [123I]IPCIT were 52% +/- 7% and 14% +/- 6%, respectively. Region of interest uptake data were normalized by injected dose and body weight. Consistent with the high density of 5-HT transporters in the midbrain and the lower 5-HT transporter affinity of IPCIT, the normalized peak specific midbrain uptake of [123I]beta-CIT (1.7 +/- 0.5) was higher than that of [123I]IPCIT (0.4 +/- 0.2). Consistent with its greater lipophilicity, [123I]IPCIT had higher nonspecific uptake, such that normalized cerebellar uptake of [123I]IPCIT was about twice that of [123I]beta-CIT. The ratio of specific to nonspecific uptake in striatum was greater for [123I]beta-CIT compared to [123I]IPCIT; however, striatal binding potentials and distribution volumes were not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Euphorigenic doses of cocaine reduce [123I]beta-CIT SPECT measures of dopamine transporter availability in human cocaine addicts.

The in vivo potency of euphorigenic doses of intravenous cocaine for displacing [123I]beta-CIT ([123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) binding to striatal dopamine transporters (DAT) was assessed in human cocaine addicts using single photon emission computed tomography (SPECT). Cocaine-dependent subjects (n = 6) were injected with [123I]beta-CIT and imaged 24 h later under equilibrium conditions. Sequential cocaine infusions (0.28 +/- 0.03 and 0.56 +/- 0.07 mg/kg) produced significant (P < 0.0005) reductions in the specific to non-specific equilibrium partition coefficient, V3" (6 +/- 6 and 17 +/- 3%), a measure proportional to DAT binding potential. Regression analysis of the logit transformed data enabled reliable determination of the Hill coefficient (0.51) and 50% displacement (ED50) dose of cocaine (2.8 mg/kg). These preliminary data suggest that cocaine produces behavioral effects in humans at measurable levels of DAT occupancy.

Carrier Proteins↗

PubMed1995

Diagnostic utility of contrast echocardiography and lung perfusion scan in patients with hepatopulmonary syndrome.

BACKGROUND & AIMS: Two modalities, contrast echocardiography and lung perfusion scan, are used to identify intrapulmonary vascular dilatation and diagnose hepatopulmonary syndrome (HPS), but a comparison of these two procedures has not been performed. The aim of this study was to compare the use of these diagnostic modalities in detecting intrapulmonary vascular dilatation and diagnosing HPS. METHODS: Forty consecutive outpatients with biopsy-proven cirrhosis had contrast echocardiography, a lung perfusion scan, and arterial blood gases analyzed. RESULTS: Fifteen of 40 cirrhotics (38%) had positive contrast echocardiogram results. Seven patients with positive echocardiogram results had gas exchange abnormalities and could be considered to have HPS (7 of 40 [17.5%]). Three of these patients were hypoxemic and had no concurrent cardiopulmonary disease, and each had positive contrast echocardiogram and lung perfusion scan results and were readily diagnosed as having HPS. The other 4 patients (3 hypoxemic and 1 normoxemic with an elevated alveolar-arterial gradient) had coexisting intrinsic lung disease and/or chest radiograph abnormalities complicating the diagnosis of HPS, and each had positive echocardiogram and negative lung scan results. The remaining 8 patients with positive echocardiogram results had normal lung scan and normal gas exchange results. No patient had positive lung scan and negative contrast echocardiogram results. CONCLUSIONS: Contrast echocardiography is the most useful screening test for intrapulmonary vasodilatation and may be positive more frequently than lung perfusion scans in patients with HPS.

Adult↗

PubMed1995

Regional brain uptake and pharmacokinetics of [123I]N-omega-fluoroalkyl-2 beta-carboxy-3 beta-(4-iodophenyl)nortropane esters in baboons.

Four N-omega-fluoroalkyl-2 beta-carboxy-3 beta-(4-iodophenyl)nortropane ester (beta-CIT-FE), N-fluoropropyl, methyl ester (beta-CIT-FP), N-fluoroethyl, isopropyl ester (IP-beta-CIT-FE), and N-fluoropropyl, isopropyl ester (IP-beta-CIT-FP)] were labeled with 125I and evaluated in baboons by dynamic SPECT regional brain imaging, measurement of pharmacokinetics in arterial plasma, and whole body imaging. The labeled tracers were prepared by iododestannylation of the corresponding 4-(trimethylstannyl)phenyl compounds in radiochemical yield 63-96% and radiochemical purity > 96%. Regional SPECT brain imaging was carried out over a period of 5 h with a Strichman 810X Brain Imager to assess regional uptake in the striatum and midbrain compared to reference regions in the occipital cortex and cerebellum; arterial blood samples were taken for analysis of metabolites by solvent extraction and HPLC. The methyl esters showed higher total and specific peak uptake in the striatum than the isopropyl esters. Midbrain uptake was uniformly lower than striatal uptake and washed out more rapidly. beta-CIT-FE had more rapid striatal kinetics than beta-CIT-FP, with specific striatal washout rates of 10-14 vs 4-6% peak/h. Biodistribution of [123I] beta-CIT-FE and [123I] beta-CIT-FP measured by whole body conjugate imaging demonstrated major uptake in the brain, liver, and GI tract, with excretion occurring through both the renal and hepatobiliary routes. Absorbed radiation does estimates based on the MIRD schema indicated highest dose rates to the urinary bladder wall and lower large intestine wall (0.7 and 0.6 rad/mCi for [123I] beta-CIT-FE and 0.7 and 0.9 rad/mCi for [123I]beta-CIT-FP, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Characterization of the dopamine transporter in nonhuman primate brain: homogenate binding, whole body imaging, and ex vivo autoradiography using [125I] and [123I]IPCIT.

IPCIT [2 beta-carboisopropoxy-3 beta-(4-iodophenyl)tropane; also designated RTI-121] is the isopropyl ester of beta-CIT [2 beta-carbomethoxy-3 beta-(4-iodophenyl) tropane]. Although beta-CIT binds to dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transporters, IPCIT has been reported to be selective for the DA transporter. IPCIT was labeled with 125I and its receptor binding to membranes prepared from baboon striatum was compared with that of [125I] beta-CIT. These studies confirmed the relative selectivity of IPCIT for the DA transporter in comparison to 5-HT and NE transporters. The nonspecific binding of [125I]IPCIT was almost four times greater than that of [125I] beta-CIT. The biodistribution of IPCIT was examined in two baboons with whole body imaging for 24-30 h after administration of 3 mCi of 123I-labeled tracer. The brain uptake peaked within the first hour at 9.2% of the injected dose and the majority of activity in the body cleared through the hepatobiliary system. The distribution of activity within the brain was examined with ex vivo autoradiography in one monkey injected with [123I]IPCIT. Activity was concentrated in the caudate and putamen and had values of 5 and 7 microCi/cm3 per microCi/g, respectively. The distribution in brain regions receiving moderately dense serotonergic innervation (e.g. superior colliculus and thalamus) had levels of activity equivalent to that in cerebellum. This study confirmed the in vitro and in vivo selectivity of IPCIT for the DA transporter but also showed that [125I]IPCIT had higher in vitro nonspecific binding than [125I] beta-CIT.

Animals↗

PubMed1995

Opiate dependence and withdrawal: preliminary assessment using single photon emission computerized tomography (SPECT).

Naloxone (0.8 mg, s.c.) effects on opiate withdrawal signs and symptoms and regional brain function were assessed in 10 methadone-maintained patients and 10 healthy subjects in a double-blind, placebo-controlled study. Regional brain function was assessed using single photon emission computerized tomography (SPECT) by evaluating the uptake of [99mTc]d,l-hexamethylpropyleneamine oxime (HMPAO) in the brain, a process related to regional cerebral perfusion. Comparisons of patients and healthy subjects after saline infusion suggested that chronic opiate dependence was associated with lower corrected activity ratios (regional count density/whole brain count density) in frontal and parietal cortices and greater activity ratios in the thalamus. Opiate-dependent patients, but not healthy subjects, developed opiate withdrawal signs and symptoms after naloxone administration. Following naloxone administration, patients undergoing opiate withdrawal exhibited lower whole brain count density than healthy subjects. They also had lower activity ratios in frontal and parietal cortices and increased thalamic activity ratios relative to healthy subjects receiving naloxone. Naloxone administration in healthy subjects, but not opiate withdrawal in patients, was associated with decreased right parietal cortex and increased right temporal cortex and left basal ganglia activity ratios. Relative to naloxone effects in healthy subjects, opiate withdrawal was associated with decreased whole brain count density and a reduced right temporal cortex activity ratio. This preliminary study reports an initial evaluation of HMPAO-SPECT imaging for assessing regional alterations in brain function during opiate dependence and withdrawal. While group differences were reported, the small magnitude of regional alterations in patients undergoing opiate withdrawal raised concern that HMPAO-SPECT methods employed were inadequate for assessing human regional brain function during phases of opiate addiction. Other emerging functional brain imaging technologies should be evaluated relative to improved HMPAO-SPECT methods for this purpose.

Adult↗