Highly sensitive method for determination of isopropyl-p-iodoamphetamine by gas chromatography with electron-capture detection.
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Biomedical subjects
Publications and source records attributed to J L Moretti.
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NPH can be reversible after cerebrospinal fluid (CSF) diversion. In the past no reliable criteria could be defined to predict the successful outcome of CSF shunting. Several authors demonstrated an increased cerebral blood flow after lumbar puncture in patients with NPH, indicating an underlying impairment of cerebral circulation autoregulation. 123I-AMP brain tomoscintigraphy was applied to 23 individuals with NPH before and after CSF drainage. Of these 23 patients, 10 underwent surgical shunting. The frontal and parietal hypoactive cortical pattern was present in NPH but not pathognomonic. Under stimulation of CSF pressure lowering, seven patients with improved outcome after shunting demonstrated an increase of cerebral perfusion in these areas, whereas a decrease of activity was found in three patients whose clinical status was unchanged after CSF diversion. This tomoscintigraphic test may be an interesting additional criterion for surgical admission.
Sixteen patients with stroke, five patients with permanent regressive ischemic neurologic deficit, and three patients with transient ischemic attacks were studied by single photon emission computed tomography performed within the first hour (early scan) and four hours (delayed scan) after injection of N-isopropyl-p-iodoamphetamine-iodine-123 (IMP). These patients were classified into three groups according to their clinical improvement three months later, and results of single photon emission computed tomography were compared with computed tomographic scan results and correlated to the clinical outcome. Regional brain hypoactivity of IMP differed in some cases between early and delayed IMP scans, showing in those cases a "redistribution" activity. The amplitude of this redistribution was significantly correlated with the clinical outcome of patients with stroke, whereas the value of hypoactivity on early IMP scan did not show such a correlation. The higher the redistribution amplitude was, the better was the clinical outcome. Comparative regional brain hypoactivity of IMP on early and delayed scans could represent a prognostic index of clinical recovery inasmuch as it gives information concerning viability of ischemic brain tissue.
Lipophilic amines are recognized as important tracers for brain imaging. Their pulmonary accumulation was a drawback for optimal concentration in the brain. We used IMP, HIPDM, IP, amphetamine derivatives to determine the relation between structure and accumulation in the lung. The incubation of phenylalkylamines in competition with 3H-Imipramine, for human lung membrane and microsomes was performed and led to the extraction of a competitive constant (KI). The results showed that the compounds can be classified in order of their decreasing affinity: Iodoamphetamine, iodoisopropylamphetamine, dimethyliodophentermine, hydroxyiodobenzyl propane diamine (HIPDM), isopropylamphetamine and amphetamine. Iodine set in the para position of the ring seemed to increase the affinity of phenylalkylamines for the lung. Adjunction of isopropyl or methyl groups to the lateral chain decreased this affinity.
p-Iodo-phentermine (IP) and two of its derivatives, N,N,-dimethyl-p-iodo-phentermine (IDMP) and N-isopropyl-p-iodo-phentermine (IIP) were synthesized and radiolabelled with iodine by isotopic exchange. They were evaluated as potential brain imaging agents and compared to IAMP biodistribution in rats did not show any superiority to IAMP.
N-isopropyl p-iodoamphetamine (IMP) demonstrates a high affinity for lung and brain during the first pass following intravenous injection. Its high brain affinity has been used to advantage for cerebral perfusion imaging, but the effects of drugs on IMP distribution could affect its utility. In this study, we determined the effects of the tricyclic antidepressant imipramine and the MAO inhibitors deprenyl and phenelzine on the biodistribution of IMP. We first determined the effect of loading dose and anesthesia on the biodistribution of IMP. In rats, biodistribution was not dependent on loading dose between 0.1 and 1.1 mg/kg. Anesthesia with thiopental and chloral hydrate depressed lung and brain IMP uptake. In rats, preloading doses of imipramine depressed lung uptake but did not result in increased brain IMP uptake; postloading doses of imipramine did not release IMP from the lung. In rabbits, simultaneous or postloading doses of imipramine resulted in release of IMP from the lung with an increase in brain activity. Both mixed A and B MAO inhibitors (phenelzine) and B selective MAO inhibitors (deprenyl) did not affect IMP distribution in rats. Based on the action of imipramine on IMP uptake and clearance in the lung, we postulate that IMP uptake and metabolism within the lung is related to the mixed function oxidase (MFO) system. As the lung is rich in the MFO system in humans, we would also predict from this study that IMP distribution in patients under antidepressant therapy would not be affected by either tricyclic or MAO inhibitor agents apart from the effect of these drugs on cerebral perfusion.
Amines like N-isopropyl-p-123I-iodoamphetamine (IMP) and hydroxy 123I-iodobenzyl propyl diamine (HIPDM) associated with brain tomoscintigraphy have proved their worth for detecting ischaemic abnormalities. Even though the chemistry of their metabolism and their biodistribution are not fully understood, their application in the study of parenchymal impairment in stroke and reversible ischaemia yields additional information compared to the other methods of imaging like CT or MRI. The concept of a steady state in brain with a wash in/wash out model has been considered especially with IMP, to explain the evolution of the activity pattern with time when comparing early and delayed images. (This review leads to foresee the prognosis of of ischaemic diseases when redistribution is taken into account.)
Early and late brain distribution of iodine-labelled N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamine (HIPDM) and iodine labelled N-isopropyl-p-iodoamphetamine (IMP) were compared in rat and one human patient with a recent stroke in the right middle cerebral artery area. In rat, an important 'redistribution' of cerebral activity was observed in various areas of the brain, mainly white matter, whereas no such observation was made with HIPDM. In the patient, the right area was hypoactive during the early SPECT with IMP and HIPDM, and redistribution was observed in the late SPECT only with IMP. We suggest that while HIPDM appears to reflect regional cerebral perfusion, IMP distribution is dependent upon metabolic brain activity.
Afferent neurons from thalamic median and intralaminar (IL) nuclei arise in the spinal cord, brain stem synapses, substantia nigra, internal pallidum and cerebral cortex, directly and through the intermediary of the reticular nucleus of the thalamus (RT). Efferent neurons terminate in the anterior thalamic nuclei, RT, striatum and cerebral cortex. Tracking methods in the rat have demonstrated that some RT neurons which project towards the IL are surrounded by endings from the posterior ventral nucleus (VP). Electrical stimulation of multiple prosencephalic structures (mainly VP) and of sensory pathways induce responses in IL of brief latency followed by inhibition. Whereas the responses appear to be related to activation of excitatory projections (under the tonic facilitating control of cerebral cortex) the inhibition phases could be related to activation of RT, since they disappear after lesion of the RT. This nucleus could act as a common final pathway of inhibitions exerted on IL in the rat. Studies in this species have demonstrated that a lateral lesion of the thalamus that includes the RT provokes the appearance in IL of abnormal neuronal hyperactivity of a tonic nature and yet still exaggerated by stimuli normally capable of inducing responses of brief duration followed by inhibition. Human studies using a tomoscintigraphic method to determine regional blood flow have shown "hyperactivity" of the thalamic region in patients with pain of central origin during a natural stimulus provoking hyperpathia. This was not observed during painful states without hyperpathia. The working hypothesis proposed is that of a central lesion inducing a hyperpathia provoking pathologic hyperactivity in certain thalamic nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)
Thirty patients with previous cerebral ischaemic accident were explored by both computerized tomography (CT) and radionuclide tomography after injection of 123I-labelled N-isopropyl-iodo-amphetamine. All lesions that were visible at CT were also visible at radionuclide tomography. However, in 7 patients with normal CT results the latter method showed areas of cerebral activity anatomically correlated with neurological signs or vascular lesions. Cerebellar diaschisis was observed in 50% of established lesions in the carotid territory. Radionuclide tomography therefore appears as a very sensitive method to be used in ischaemic pathology with transient or regressive accidents.
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The performance of a slant-hole collimator was compared with that of a standard straight-bore, low-energy collimator for tomographic imaging of I-123-iodinated amine brain agents. Improved in-slice resolution was due to the greater proximity between collimator and the subjects' heads. We conclude that high quality tomographic images of the brain can be obtained from rotating cameras equipped with slant-hole collimators.
Among the iodophenylalkylamines studied and labelled with iodine 125 or iodine 123, N-isopropyl-iodo-amphetamin (IAMP) was selected and proposed as tracer for blood flow, a "chemical embolus" having almost 100% extraction in the brain. A new way of obtaining N-isopropyl-p-iodo-amphetamin is proposed and the easily-applied exchange reaction with iodine 125 or 123 gives a product with a radiochemical purity of more than 96% and an unexchanged radioactive iodine content of less than 1%. The pharmacokinetic study of this product in the Wistar rat showed distribution in three compartments and the appearance of a steady state by the fourth minute. The target organs are the lungs, liver and brain. The latter receives 3% of the radioactivity and the autoradiographic study shows that the early distribution in the brain for IAMP closely equals the blood flow as found by a diffusible indicator. In the first hour, the redistribution is very low and at this time although IAMP is proposed for the study of regional blood flow, it does not exactly determine the flow but rather mirrors cell activity.
Tomographic maps of local cerebral blood flow (CBF) were obtained with xenon-133 and with isopropyl-amphetamine-iodine-123 (IMP) in 11 subjects: one normal, two tumor cases, and eight cerebrovascular cases. A highly sensitive four-face, rapidly rotating, single-photon emission tomograph was used. The Xe-133 flow maps are essentially based on the average Xe-133 concentration over the initial 2 min during and after an inhalation of the inert gas lasting 1 min. These maps agreed very well with the early IMP maps obtained over the initial 10 min following an i.v. bolus injection. The subsequent IMP tomograms showed a slight decrease in contrast amounting to appr. five percentage points in the CBF ratio between diseased and contralateral areas. It is concluded that Xe-133 is more practical: low cost, available on a 7-day basis, easily repeatable, quantifiable without the need for arterial sampling, and with low radiation exposure to patient and personnel. On the other hand, IMP gives an image of slightly higher resolution. It also introduces a new class of iodinated brain-seeking compounds allowing, perhaps, imaging of other functions more important than mere blood flow.
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