N. P. L. G. Verhoeff

In vivo characterisation of 3-iodo-6-methoxybenzamide 123I in humans.

Abstract3-Iodo-6-methoxybenzamide (123I-IBZM), a new Dopamine D2 receptor ligand, was used in conjunction with SME 810 brain tomography to study six subjects (one normal volunteer, four schizophrenics and one DAT patient). Initial Dynamic SPET was followed by multislice SPET. High-resolution images of the D2 receptor distribution in the basal ganglia were obtained. The specific binding in D2 receptors of the basal ganglia is highest from 2–4 h p.i. Patients on anti-psychotic drugs showed significantly lower specific binding. Dopamine D2 brain receptor availability in man may now be studied with SPET. Continuous data acquisition with single slice tomography is particularly important in the study of this type of radiotracers.

Evaluation of a multicentre study with Iomazenil--a benzodiazepine receptor ligand.

After showing in an earlier publication that Iomazenil is a potent benzodiazepine receptor antagonist, the substance has been distributed to 11 clinical centres in Europe for further tests. The protocol asked for volunteers, epileptic cases and patients with Alzheimers disease. Prior to the Iomazenil examination, flow images by perfusamine or HMPAO were required, and as comparative methods EEG, computed tomography (CT) and magnetic resonance imaging (MRI) were performed. The results allowed first the determination of the normal distribution of the benzodiazepine receptors in the human brain. The highest uptake was found in medial occipital cortex. Second, the evaluation of the epileptic cases shows a 100% positive prediction value for Iomazenil compared to 92% for flow images. Negative prediction values were calculated as 81% for Iomazenil and 54% for flow images. Furthermore, one group reported the successful diagnosis of Alzheimers disease at an early stage. The visual image examination was tentatively compared to a more objective semiquantitative one based on quotients of corresponding left/right regions of interest. This semiquantitative method has not proved successful yet, but the problems have been identified. A more precise protocol for further studies is therefore proposed.

Dynamic SPECT in two healthy volunteers to determine the optimal time for in vivo D2 dopamine receptor imaging with 123I-IBZM using the rotating gamma camera.

Dynamic SPECT was performed in two healthy male volunteers with a single slice brain dedicated camera (Strichman Medical Equipment 810, first study) and a rotating gamma camera (Siemens Dual Rota ZLC37, second study) to obtain information about the optimal imaging time for the dopamine D2 receptor specific ligand 123I-(S)-(-)-2-hydroxy-3-iodo-6-methoxy-N[(1-ethyl-2-pyrrolidinyl) methyl]-benzamide (123I-IBZM). Count rates in the basal ganglia and in several cerebral cortical regions were used to define specific and aspecific binding, respectively. On the basis of the first study, 90-150 min seemed the optimal time for rotating gamma camera 123I-IBZM-SPECT. On the basis of the second study the optimal period was considered to be 60-120 min. It is recommended to apply the same imaging time after injection in a protocol to all patients and volunteers as otherwise a comparison may not be reliable.

In vitro and in vivo D2-dopamine receptor binding with [123I]S(−)iodobenzamide ([123I]IBZM) in rat and human brain

As a promising dopamine D2-receptor imaging agent for single photon emission computerized tomography (SPECT), [123I](S)-(-)-2-hydroxy-3-iodo-6-methoxy-N [(1-ethyl-2-pyrrolidinyl)methyl]benzamide ([123I]IBZM) has recently been synthesized in a modified way along with its precursor, S(-)BZM, and the stereoisomer R(+)BZM. The present study applied this new product to investigate in vitro and in vivo D2-receptor binding in rat brain and in postmortem human brain. In vitro saturation binding curves with [123I]IBZM for rat crude striatal membrane preparations yielded an affinity constant (Kd) of 0.28 nM confirming data in the literature. Displacement curves revealed an order of increasing potency as follows: R(+)BZM less than S(-)sulpiride = less than S(-)BZM less than S(-)IBZM. A similar order was obtained when [3H]spiperone was used as ligand. For human putamen and caudate nucleus membranes slightly higher Kd values (0.49 nM) were obtained. Rank order of displacing potency for the various drugs was similar to that found in the rat preparations. In vivo uptake of [123I]IBZM in rat brain following injection of 50 microCi (12-16 pmol) in the tail vein revealed an increase in the striatum-to-cerebellum ratio from 1.5 at 5 min to 6.9 at 2 h. The olfactory tubercle-to-cerebellum ratio was also raised from 1.6 to 3.3. Other brain regions tested failed to show statistically significant enhancements. Coinjection of 40 nmol S(-)IBZM, 4 mumol S(-)BZM or 200 nmol haloperidol displaced [123I]IBMZ when tested at 90 min. The use of 4 mumol R(+)BZM resulted in minor displacement only, demonstrating that stereospecificity of the displacement was present in vivo and in vitro. Displacements were also observed in substantia nigra and pons-medulla oblongata, but not in hippocampus or frontal and occipital cortex. The data provide the required background needed in order to initiate in vivo binding studies for D2-receptors in basal ganglia of human patients using [123I]IBZM in SPECT analyses.

Imaging of dopamine D2 and somatostatin receptors in vivo using single-photon emission tomography in a patient with a TSH/PRL-producing pituitary macroadenoma

A 28-year-old man with a thyroid stimulating hormone/prolactin (TSH/PRL)-secreting pituitary macroadenoma is discussed in relation to dopamine D2 and somatostatin receptor single-photon emission tomography (SPET). The patient presented with decreased vision in the left eye as a result of a temporal visual field defect and with mild hyperthyroidism. Medical therapy was tried. A test dose of both octreotide and bromocriptine resulted in an acute reduction in serum levels of TSH, α-subunits and PRL, whereas there was no response to TRIAC. Somatostatin and dopamine D2 receptors were present on the tumour as visualised by SPET with the ligands indium-111 diethylene triamine penta-acetic acid (DTPA)-octreotide (111In-SMS) and iodine-123 iodobenzamide (123I-IBZM), respectively. Therefore, treatment with octreotide 150 μg t.i.d. subcutaneously and bromocriptine 10 mg b.i.d. orally was given for > 12 and > 6 weeks, respectively. Following this treatment the visual defects disappeared, although tumour size, as measured by CT scanning, and serum TSH levels did not decrease. SPET with 111In-SMS and 123I-IBZM after therapy revealed no change or a possible increase in somatostatin receptor binding potential and a possible decrease in dopamine D2 receptor binding potential. The lack of long-term effects of the medical treatment is discussed. It is concluded that a high somatostatin and dopamine D2 receptor binding potential in vivo in a TSH/PRL-producing adenoma does not necessarily predict a successful outcome of medical treatment.

Dosimetry of iodine-123 iodobenzamide in healthy volunteers

The distribution of the dopamine D2-receptor specific ligand iodine-123 (S)-(−)-2-hydroxy-3-iodo-6-methoxy-N[(1-ethyl-2-pyrrolidinyl)methyl]-benzamide (1231-IBZM) was investigated in human adults from whole-body scans, blood samples and urine collected up to 48 h after injection. Results from the present study performed in six healthy volunteers were combined with those of five volunteers from a previous study. Using the brain, liver, lungs and spleen as source organs, the MIRD method was applied to calculate the absorbed radiation dose of the radioligand in various organs. The thyroid (despite blockage), gall-bladder wall, large intestinal walls and spleen received the highest absorbed doses. The average effective dose equivalent of 123I-IBZM for adults was estimated to be 0.034 mSv/MBq. The absorbed dose to the thyroid may be a limiting factor for 1231-IBZM studies in children.

Quantification of central benzodiazepine receptor binding potential in the brain with 123I-iomazenil SPECT: technical and interobserver variability

Factors contributing to the quantification of the central benzodiazepine receptor binding potential in vivo using 123I-iomazenil and single photon emission computed tomography (SPECT) were analysed in phantom studies and in volunteers. SPECT was performed with the SME810 multidetector system. The Hoffman three-dimensional brain phantom was used to investigate linearity and reproducibility of SPECT results using different 123I activity concentrations. Dynamic and multislice SPECT scans were performed in nine healthy volunteers between 0 and 270 min after injection of 110 MBq 123I-iomazenil. Displacement studies were performed in three volunteers using 1 mg flumazenil administered intravenously (i.v.) at 250 min postinjection (p.i.). Regions of interest (ROIs) over the cerebral cortex and various subcortical nuclei were either fixed areas based on a stereotaxic brain atlas, or manually drawn, based on 60% isocontour lines. Interobserver variability of the ROI data and ratios derived from those data were estimated for two independent observers. The brain phantom measurements showed linearity with respect to 123I concentration and good reproducibility. The interobserver study showed a reasonable interobserver reliability for the large fixed ROIs. The displacement study showed about 50% displacement in all ROIs. Concentrations of 123I-iomazenil in the brain can be measured reliably with the SME810. Large fixed ROIs based on a stereotaxic atlas may be used reliably for quantification. The level of 4 cm above the cantomeatal line does not provide a useful reference region with a very low central benzodiazepine receptor binding potential.

Dosimetry of iodine-123 iomazenil in humans

The distribution of the central benzodiazepine receptor specific ligand iodine-123 iomazenil was investigated in seven human adults from whole-body scans, blood samples and urine collected up to 24 h after injection. Using 12 source organs, the MIRD method was applied to calculate the absorbed radiation dose of the radioligand in various organs. The urinary bladder wall (0.15 mGy/MBq), lower large intestinal wall (0.071 mGy/MBq) testes (0.044 mGy/MBq) and upper large intestined wall (0.038 mGy/MBq) received the highest absorbed doses. The average effective dose equivalent of 123I-IBZM for adults was estimated to be 0.033 mSv/MBq.

Dopamine D2-Receptor Imaging with 123I-Iodobenzamide SPECT in Migraine Patients Abusing Ergotamine: Does Ergotamine Cross the Blood Brain Barrier?

Two migraine patients were studied by in vivo SPECT using the dopamine D2–receptor specific radioligand 123I-3–iodo-6–methoxybenzamide (123I-IBZM) during ergotamine abuse and after withdrawal. Results were compared with 15 healthy controls. Striatum/cerebellum and striatum/occipital cortex ratios of count rate density were calculated as a semiquantitative measurement for striatal dopamine D2–receptor binding potential. No differences were found in striatal uptake of 123I-IBZM between healthy controls and the patients when on or off ergotamine. Preliminary evidence suggests that ergotamine may not occupy striatal dopamine D2–receptors to a large extent and thus may not cross the blood brain barrier in large quantities.

Focus localization in patients with partial epilepsy with 99Tcm-HMPAO SPECT under continuous surface EEG monitoring

Our study was aimed at determining the validity of 99Tcm-HMPAO single photon emission computed tomography (SPECT) in the localization of the epileptogenic focus by correlating this diagnostic method with other auxiliary investigations such as surface EEG and X-ray transmission computed tomography (CT). Twenty-eight patients with partial epilepsy and spontaneous memory complaints were assessed with a 21-channel EEG recorded during psychometric evaluation of the memory complaints and with a 12-channel EEG during 99Tcm-HMPAO SPECT. No significant agreement was observed for total focus localization by the two EEGs, CT or SPECT. The EEGs were highly reproducible. Frontal and temporal pathology on CT resulted in frontal and temporal cold spots on SPECT on the same side in six patients. In addition, SPECT demonstrated frontal, temporal or posterior temporal-inferior parietal cold spots in nine patients without accompanying pathology on CT. It is concluded that CT and SPECT may provide complementary anatomical and functional information, respectively, to the EEG. Furthermore, SPECT may be complementary to CT in visualizing functional deficits without an anatomical correlate. The value of SPECT studies in partial epilepsy may be improved by increasing the resolution of the SPECT system and by simultaneous EEG monitoring.