Radiopharmaceuticals labelled with bromine isotopes.
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Biomedical subjects
Publications and source records attributed to C Loc'h.
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Using positron tomography and 76Br-labeled bromospiperone, a neuroleptic drug with high affinity for the dopamine (DA) receptors, we have estimated the specific binding of the radiotracer to striatal DA receptors in seven patients suffering from progressive supranuclear palsy. Compared with age- and sex-matched control subjects, we found a significant (p less than 0.02) decrease of the striatum-cerebellum uptake ratio in progressive supranuclear palsy patients, suggesting loss of striatal DA receptors. This in vivo study confirms recent postmortem data on progressive supranuclear palsy patients and provides an explanation for the lack of benefit from L-DOPA and DA agonists in this condition, despite reduced nigrostriatal dopaminergic function.
The brain regional distribution and kinetics of [76Br]bromospiperone, a derivative of a neuroleptic (spiperone) labeled with the positron emitter bromine-76, were studied by time-of-flight tomography after i.v. injection in man. In a control subject the kinetic distribution study showed an accumulation of radioactivity which reached a maximum 3 h postinjection in the frontal cortex and cerebellum regions and 4-5 h postinjection in the basal ganglia. Thereafter the striatal activity remained essentially constant over a period of 25 h. In a group of 13 control subjects, the mean value for the striatum-to-cerebellum ratio, at 4.5 h postinjection, was 1.84 (S.D. 0.21). In two schizophrenics treated with high doses of haloperidol, this ratio was found to be only 1.22. These data indicate that radiolabeled bromospiperone is very suitable for human pharmacological or pathological investigations of the central dopaminergic system.
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The measurement of cerebral blood flow (CBF) by continuous C15O2 inhalation has only been validated previously by indirect experimental protocols. In the present study using baboons, these measurements were compared directly with those obtained by injection of 68Ga-labelled serum-albumin microspheres in the left cardiac ventricle. Using a modified labelling technique, no elution of 68 Ga occurred in vivo. Both methods provided similar regional CBF values, which could be described by a significant linear correlation (CBFCO2 = 0.82 CBFmicrospheres + 5.7; P less than 0.001). The validity of the labelled-microsphere-injection method was verified. The feasibility of stable in vivo labelling of 68Ga to serum-albumin microspheres provides a reference method for organ blood-flow measurements using positron-emission tomography.
Functional images of regional intracellular pH (pHi) and of fractional volume of extracellular water (FVECW) were obtained in 10 patients with recent hemispheric infarction (between 10 and 19 days after onset of symptoms) using positron emission tomography (PET). The volume of extracellular water relative to that of total water was evaluated in each pixel of the PET scan 7-8 h after injection of 76Br. The pHi image was calculated from the data obtained after injection of [11C]5,5-dimethyl-2,4-oxazolidinedione and from the FVECW image. Regional CBF, oxygen extraction, and oxygen metabolism were also measured in the same patients. In normal hemisphere, mean +/- SD values for FVECW and pHi were 0.12 +/- 0.01 and 6.86 +/- 0.11, respectively. FVECW was increased in the infarcted area in most patients. pHi was increased in the infarct in seven patients and unchanged in three. The increase in pHi was not correlated with changes in FVECW, CBF, or CMRO2, but there was a significant correlation with the decrease in oxygen extraction fraction in the same region. Thus, the decreased H+ content in the infarcted area was correlated with the occurrence of perfusion in excess of metabolic demand. An alkaline shift in pHi enhances the glycolysis rate and could explain why the glucose metabolism is less affected than the oxygen metabolism in recent cerebral infarction. The pHi measured in the infarct could represent mainly the pHi of phagocytic cells that use aerobic glycolysis to synthesize hydrogen peroxide.
Bromine-76 labeled bromospiperone has been prepared with a very high specific activity (greater than 1 Ci/mumole). In-vivo studies in rat corroborated by PET studies in baboon have shown that the regional concentration of this radioligand parallels the morphologic distribution of dopamine receptors and that its binding in the striatum is saturable and displaceable. Tomographic images show a clear delineation of the striatal region 2.5 hours after administration of the radioligand.
Neon 19, 17-second positron-emitting radioelement, is produced continuously by 23MeV alpha particle bombardment of oxygen. For a 12 muA particle current the method of preparation described delivers 14 mCi of neon 19 per min to the functional exploration room. The radiochemically pure radioactive gas is diluted in air and breathed continously by the patient lying under a positron tomographic camera. The regional lung ventilation distribution is obtained on 2 cm thick sections of organ with a transverse resolution of 17 mm. Quantification of the ventilation output per unit lung volume is contemplated.
To meet the needs created by the rapid development of positron tomographic techniques, a new Ge-68 leads to Ga-68 generator has been developed. By elution under reduced pressure, this tin dioxide/1 N HCl generator provides a sterile solution of Ga-68 in ionic form, ready for use in the preparation of many radiopharmaceuticals. Since the Ga-68 recovery yield is high (75--80%) and the elution time very short (less than 2 min), these products possess maximum activity. Owing to its very slight Ge-68 leakage (less than 0.0002% per elution), the tin dioxide/HCl generator is long-lasting and, more importantly, the radiotoxicity of the labeled derivatives is kept to a minimum. The ionic Ga-68 obtained in this way has been used to label several radiopharmaceuticals.
Evaluation of oligonucleotides for biomedical applications requires different in vivo and in vitro approaches (pharmacokinetics, biodistribution, macro- and microimaging, metabolism,.), that are performed with different radioisotopes according to the temporal and spatial resolution needed. A method to introduce radioactive isotopes of halogens (fluorine, bromine, and iodine) in a small and stable molecule has been developed. Radiosynthons can then be conjugated with any given oligonucleotide in one step to create the appropriate radiotracer. This general radiolabeling procedure for oligonucleotides is efficient to synthesize (18)F-, (76)Br-, and (125)I-oligonucleotides for biological needs. Applications of the method to biodistribution, metabolism, in vivo and ex vivo imaging of (125)I- and (18)F-labeled oligonucleotides are reported.
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