Autoradiographic and SPECT imaging of cerebral opioid receptors with an iodine-123 labeled analogue of diprenorphine.

The feasibility of imaging cerebral opioid receptors by single photon emission computed tomography (SPECT) has been established in baboon using a novel analog of diprenorphine (DPN) radiolabeled with iodine-123. The radioligand, [123I]-O-IA-DPN (C6-O-[123I]iodoallyl-DPN), was prepared in good yield (80%) with high radiochemical purity (>97%) and high specific radioactivity (>2,400 mCi/micromol). In ex vivo autoradiographic studies, with and without naltrexone blockade, [123I]-O-IA-DPN specifically labeled opioid receptors throughout the mouse brain. Nonmetabolized radioligand accounted for >90% of the signal observed in extracts of whole mouse brain. SPECT imaging trials showed that [123I]-O-IA-DPN selectively localized in regions of baboon brain known to have high densities of opioid receptors, such as striatum, thalamus, and temporal cortex. A much lower level of radioligand uptake and retention was noted for cerebellum, a region with few opioid binding sites. Pretreatment with naltrexone (6.5 pmol/kg) blocked [123I]-O-IA-DPN binding in all brain regions. Using naltrexone blockade to define the nonspecific component for a given region of interest, total to nonspecific binding ratios increased linearly (r > or = 0.98) over the SPECT study with maximal values for striatum (9.8), thalamus (7.1), and temporal cortex (6.9) reached at the last time point investigated (3.5 h). Specific binding for these regions, assessed as the difference between regional SPECT activity for the control and blocked states, proved irreversible over the observation period. By the end of the time course, specific [123I]-O-IA-DPN binding was >85% of total radioactivity in regions rich in opioid receptors and 62% of total radioactivity in cerebellum. The aggregate data are consistent with visualization of multiple opioid receptor types. Thus, [123I]-O-IA-DPN should prove useful for SPECT studies within the constraints imposed by a lack of innate selectivity for a single type of brain opioid receptor.

Clinicopathological correlation of technetium bone scan in vascularization of hydroxyapatite implants. A primate model.

OBJECTIVES: To report the histopathological and bone scan characteristics of the stages of hydroxyapatite fibrovascular integration and to consider the implications for the timing of peg drilling in a primate model. DESIGN: Three monkeys received hydroxyapatite implants covered only anteriorly with a fascia lata button to which the rectus muscles were sutured. Weekly bone scans were evaluated quantitatively and qualitatively. The orbits were harvested at 2, 4, and 8 weeks and examined histopathologically. RESULTS: Quantitatively, the implant's technetium uptake increased, then reached a plateau by 4 weeks. Peripheral uptake was present on the images and histologically at 2 weeks. When bone scan images suggested complete vascularization by the fourth week, the implant was 99% vascularized histologically. Completion of vascularization was ascertained at 8 weeks, without further discernible changes in the bone scans. CONCLUSIONS: The technetium bone scan is sensitive to the vascularization of the hydroxyapatite implant and discerns when complete vascularization is approached. This primate study models closely the clinical findings we have recently reported. We advocate at least a 4-week interval between the time the bone scan suggests full vascularization and peg drilling.

Quantitative measurement of vascularization and vascular ingrowth rate of coralline hydroxyapatite ocular implant by Tc-99m MDP bone imaging.

Complete fibrovascular ingrowth of the hydroxyapatite ocular implant is necessary for peg drilling, the secondary procedure that couples the mobile sphere to the ocular prosthesis providing it with motility. This study was conducted to determine the usefulness of the bone scan for the evaluation and relative quantification of the vascularization of coralline hydroxyapatite ocular implants. In 23 patients (32 scans), vascularization of the ocular implant was measured by three-phase bone scintigraphy. There were 16 patients with left, and 7 with right orbital implants. At followup 0.5 to 8 months after successful hydroxyapatite implantation, the mean implant to normal intraorbital activity ratio on delayed bone scans in anterior view was 2.73 +/- 0.73 (mean +/- SD) with a range of 1.42-4.2. The normal right to left and left to right intraorbital bone activity ratios determined in anterior view from 10 normal delayed bone scans were 0.98 +/- 0.05 (mean +/- SD) and 1.02 +/- 0.05 (mean +/- SD) respectively, with a range of 0.93-1.07. The difference of the activity (count) ratios among the successfully implanted group and normals was statistically significant (P < 0.0001). A hydroxyapatite ocular implant to contralateral intraorbital bone activity ratio of greater than 1.12 with a homogeneous tracer distribution throughout the implant suggests adequate and diffuse vascularization is present. The progressive increase in activity ratio of the orbital implants seen in the early postimplantation period, which is indicative of the progression of vascularization, reaches a plateau after 1 month and remains relatively stable thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)

Multimodality correlative study of canine brain tumors. Proton magnetic resonance spectroscopy, positron emission tomography, and histology.

RATIONALE AND OBJECTIVES: Structural/functional relationships in an induced canine brain tumor were studied using proton-magnetic resonance spectroscopy (1H-MRS), positron emission tomography (PET), and histology. METHODS: Proton-MRS and PET data of implanted canine brain tumors were correlated with quantitative analysis of the tissue composition within the MRS and PET regions of interest (ROIs). Linear regression analysis was employed to correlate the 1H-MRS and PET data with the percent tumor and the percent total lesion (comprising tumor plus associated pathology ie, edema, cysts, hemorrhage, inflammation) within the ROI. RESULTS: Using 1H-MRS, N-acetyl aspartate concentrations were indirectly correlated with the amount of tumor (P = .058), as well as the amount of tumor plus associated pathology (P = .032) within the ROI. Total creatine concentrations were indirectly correlated with the amount of tumor and the amount of tumor plus associated pathology within the ROI (P < .05). Lactate concentrations were directly correlated with the amount of tumor (P = .053) and the amount of tumor plus associated pathology (P = .058) within the ROI. Using PET, Oxygen metabolic rates were indirectly correlated with the amount of tumor and with the amount of tumor plus associated pathology within the ROI (P < .05). Glucose metabolic rates were directly correlated with both the amount of tumor and with the amount of tumor plus associated pathology at P < .05. Proton-MRS measured concentrations of choline and PET measured values for blood flow, and oxygen extraction showed correlations with the amount of tumor and with the amount of tumor plus associated pathology at P > or = .08. CONCLUSIONS: The PET and MRS data were complementary with respect to suggesting anaerobic glucose metabolism for the tumor. Unlike other tumors, no increase in choline was noted in the canine tumor.

Comparison of [11C]diprenorphine and [11C]carfentanil in vivo binding to opiate receptors in man using a dual detector system.

A simple dual detector coincidence system was used to measure the binding of [11C]carfentanil and [11C]diprenorphine to opiate receptors in normal volunteers before and after the administration of naloxone. Total radioactivity without naloxone and the ratio of total/non-specific radioactivity was 2 times greater for [11C]diprenorphine than [11C]carfentanil. The dose of naloxone required to maximally block specific [11C]diprenorphine binding was 10 times that for [11C]carfentanil, indicating that [11C]diprenorphine labels opiate receptor subtypes in addition to mu opiate receptors.

Noncompartmental and compartmental modeling of the kinetics of carbon-11 labeled pyrilamine in the human brain.

The kinetic pattern of a 11C-labeled histamine H1 receptor antagonist, [11C]pyrilamine, was investigated in the human brain by factor analysis of dynamic PET studies. Tissue time activity curves were also processed by compartment model curve fitting preceded by deconvolution analysis. Factor analysis revealed two statistically significant and physiologically meaningful kinetic patterns: one for specific and another for nonspecific binding of the radioligand. From these two factors a compartment model containing two tissue compartments (one for specific binding and another for nonspecific binding and free ligand) was constructed. The two-compartment model was also supported by the impulse response function, which was obtained by deconvolution and showed two components. The factor image constructed from factor two demonstrated a distribution pattern characteristic for brain regions rich (frontal, parietal, and temporal lobes) or poor (occipital lobe and cerebellum) in H1 receptors. Blockade of H1 receptors with unlabeled pyrilamine, diphenhydramine, or hydroxyzine caused a significant reduction of this factor. Blockade produced no significant changes in factor one representing nonspecific binding. We conclude that the kinetics of [11C]pyrilamine in the brain can be described by two tissue compartments, one related to the distribution of the H1 receptors. Factor analysis of dynamic studies can be used to locally separate these two compartments, for identification of regions rich and poor in H1 receptors and for noninvasive quantitative investigation of the effects of H1 receptor blockers such as pyrilamine, diphenhydramine, or hydroxyzine.

Reduced left ventricular cavitary activity ("black hole sign") in thallium-201 SPECT perfusion images of anteroapical transmural myocardial infarction.

Apparently reduced left ventricular (LV) cavitary thallium activity in both planar and tomographic perfusion images has been previously observed by these and other investigators. With single-photon emission computerized tomography, we have clinically noted that this "black hole sign" was associated with an aneurysm in the setting of a transmural anterior or anteroapical perfusion defect. We have now prospectively studied the etiology and predictive value of this sign in 84 consecutive patients with an anterior, anteroapical transmural perfusion defect. Of the 84 patients, 49 had both LV aneurysm (confirmed by contrast ventriculography, echocardiography or gated blood pool studies) and a black hole sign. Only 1 patient with an aneurysm did not have the black hole sign, and 2 without aneurysm did. Thus, it is concluded that this sign is highly accurate in diagnosing LV aneurysm. Because thallium-201 single-photon emission computerized tomography imaging is often performed as one of the first diagnostic tests soon after myocardial infarction, this has important clinical management implications.

Imaging histamine H1 receptors in the living human brain with carbon-11-pyrilamine.

The brain distribution and kinetics of the H1 receptor antagonist, carbon-11-pyrilamine (11C-pyrilamine) were examined in vivo in two baboons and one human by positron emission tomography. After i.v. administration of the tracer, brain activity peaked within 20 min after injection and subsequently decreased, reflecting reversible binding to the receptor. Pretreatment with 1 mg/kg diphenhydramine reduced the brain activity at 70 min by 33%, 29%, 26%, and 23% of the control values in frontal cortex, temporal cortex, hippocampus, and cerebellum, respectively. Coinjection of 1 and 5 mg/kg cold pyrilamine reduced the activity at 70 min by 40%, 36%, 34%, and 30% in frontal, temporal, hippocampus and cerebellum, respectively. The in vivo specific binding to the H1 receptors in different brain regions at 70 min after injection correlated with the in vitro H1 histamine receptors distribution in human brain tissue obtained at autopsy, with high values in the frontal and temporal cortex and low values in cerebellum and brain stem. In the healthy human volunteer study, the value of washout of radioactivity increased by about 50% after injection of 0.7 mg/kg diphenhydramine.

Immediate effect of expiratory loading on left ventricular stroke volume.

While the steady-state effects of positive pleural pressure on the circulation have been extensively studied, less is known about the immediate effects of positive intrathoracic pressure on cardiac dynamics. Therefore, we performed electrocardiographically gated radionuclide ventriculography with a respiratory gating technique in nine healthy subjects during quiet breathing and during expiration against a 24 cm H2O expiratory threshold load. During expiration, respiratory loading caused an increase in stroke counts by 29.4% (p less than .001) due to an increase in end-diastolic counts of 26.1% (p less than .001). End-systolic counts also rose 18.8% (p less than .05). The ejection fraction did not change significantly. These findings indicate that the increase in left ventricular stroke volume that occurs during the first 1 or 2 beats of a loaded expiration is due to an increase in left ventricular filling and not to augmentation of left ventricular ejection. This immediate increase in pulmonary venous return may reflect increased distensibility of the left ventricle due to decreased filling of the right ventricle.

Simplified detection system for neuroreceptor studies in the human brain.

A simple, inexpensive dual-detector system has been developed for measurement of positronemitting receptor-binding drugs in the human brain. This high efficiency coincidence counting system requires that only a few hundred microcuries of labeled drug be administered to the subject, thereby allowing for multiple studies without an excessive radiation dose. Measurement of the binding of [11C]carfentanil, a high affinity synthetic opiate, to opiate receptors in the presence and in the absence of a competitive opiate antagonist indicates the potential utility of this system for estimating different degrees of receptor occupation in the human brain.

Right ventricular ejection fraction measured by first-pass intravenous krypton-81m: reproducibility and comparison with technetium-99m.

Study of the effects of various diseases and therapeutic manipulation of pulmonary vascular resistance on the right ventricle has been restricted by methodologic limitations. The radioactive gas in solution, krypton-81m was used to study the right ventricle and the technique was compared with a technetium-99m method. In 22 subjects, first-pass krypton-81m right ventricular ejection fraction, acquired both in list mode and electrocardiogram-gated frame mode, correlated well (r = 0.81 and 0.86, respectively, p less than 0.01) with that determined by technetium-99m first-pass studies over a broad range of ventricular function. The reproducibility of the technique was excellent (r = 0.84 and 0.95 for each acquisition mode, respectively). Krypton-81m first-pass studies provide accurate and reproducible estimates of right ventricular function. Use of krypton allows multiple measurements, with or without perturbations, over a short period of time.

Mechanism of decreased left ventricular stroke volume during inspiration in man.

Radionuclide ventriculography was performed in 15 healthy subjects during quiet breathing and during inspiration against a 24 cm H2O threshold load with a respiratory gating technique. Inspiratory threshold loading caused an inspiratory decrease in ejection fraction from 64% to 59% (p less than .001). Stroke counts proportional to stroke volume decreased by 9.6% (p less than .02) due to an increase in end-systolic counts of 15.9% (p less than .05). End-diastolic counts decreased in four subjects and increased in three subjects, but the mean counts did not change significantly. These findings suggest that negative pleural pressure causes an impediment to left ventricular ejection comparable to an increase in arterial pressure. Respiratory gating of radionuclide ventriculography during loaded breathing is suggested as a controlled stress on the ventricle for diagnostic purposes.

Evaluation of indium-111 as a new high photon yield gamma-emitting "physiological" platelet label.

In order to evaluate indium-111 (111In) as a "physiological" platelet label, rabbit platelets were labeled in vitro with 111In-8-hydroxyquinoline. The in vivo behavior of 111In labeled platelets was then compared with that of chromium-51 51Cr) labeled platelets in the rabbit. Several important features were evident. First, unlike 51Cr, reasonable platelet labeling efficiency could be achieved with 111In, even when the platelets were suspended in small amounts of autologous plasma. Second, the initial recovery of platelets at 20 minutes after infusion was significantly higher for the 111In labeled platelets than for 51Cr labeled platelets, providing the platelets were suspended and "washed" in plasma. Third, the mean survival time of 111In labeled platelets, as estimated using four different mathematical models, was comparable with that of 51Cr platelets. Finally, the high photon yield of gamma emitting 111In, unlike 51Cr, permits quantitative gamma camera imaging of the in vivo distribution of labeled platelets. Thus, this nuclide possesses advantages as a platelet label that will foster statistically more accurate kinetic research as well as quantitative in vivo distribution studies in humans.

The nuclear stethoscope: a simple device for generation of left ventricular volume curves.

Initial evaluation has begun of a system for displaying left ventricular time-activity curves, relating the intraventricular content of radioactivity with the cardiac cycle as determined by the patient's electrocardiogram. Major problems include proper positioning of the detector, correction for background radioactivity outside the ventricle and calibration of the device to permit conversion of measurement of radioactivity to measurement of ventricular volumes.

A test for patency of the cystic duct in acute cholecystitis.

A procedure was devised to quickly and reliably determine the patency of the cystic duct in patients suspected of having acute cholecystitis. First the gallbladder was stimulated to empty by a cholecystokinin injection. Thirty minutes later a radiolabeled biliary marker, either 150 muCi 131-I rose bengal or 2 mCi 99-mTc dihydrothioctic acid, was injected, and the accumulation of radioactivity in the liver and gallbladder regions was monitored by external gamma emission imaging and recording devices. The images of diagnostic importance were obtained between 60 and 90 minutes after injection of the tracer. Thirty-nine patients with acute abdominal pain were studied. Ten patients who had acute cholecystitis failed to show gallbladder accumulation of radioactivity, reflecting the cystic duct obstruction that initiates this disease. Twenty-nine patients having a variety of other diseases all showed gallbladder accumulation of activity, indicating in each patient that the cystic duct was patent. No significant adverse effects were noted. We conclude that the procedure is a useful adjunct to the clinical and roentgenographic evaluation of patients with acute abdominal pain.