Ligandin binding phthalein complexone complex of technetium for hepatic function studies

In our pursuit for liver functional diagnosis, development of bifunctional radiopharmaceutical containing iminodiacetic acid (IDA), as the technetium chelating site along with phthalein or fluorescein structure, the skeleton of BSP and Rose Bengal, long used for the assessment of liver function is considered. Among the various PC, PPC, TPC and calcein IDA derivatives commercially available, 99mTc-PC (PC: 3,3'-bis(N, N-dicarboxymethylaminomethyl)o-cresolphthalein) showed the highest hepatobiliary excretion. The functionality of the various technetium labeled phthalein and fluorescein IDA derivatives was evaluated by competitive BSP binding studies and by comparative binding with the hepatocyte specific protein, ligandin.     

Biokinetic and dosimetric studies of Re-hyaluronic acid: a new radiopharmaceutical for treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has very limited therapeutic options. Recently, it has been found that hyaluronic acid (HA) shows selective binding to CD44 receptors expressed in most cancer histotypes. Since the trend in cancer treatment is the use of targeted radionuclide therapy, the aim of this research was to label HA with rhenium-188 and to evaluate its potential use as a hepatocarcinoma therapeutic radiopharmaceutical.

Methods

¹⁸⁸Re-HA was prepared by a direct labelling method to produce a ReO(O-COO)₂-type coordination complex. ¹⁸⁸Re-HA protein binding and its stability in saline, phosphate buffer, human serum and cysteine solutions were determined. Biokinetic and dosimetric data were estimated in healthy mice (n=60) using the Medical Internal Radiation Dose methodology and mouse model beta-absorbed fractions. To evaluate liver toxicity, alanine aminotranferase (AST) and aspartate aminotranferase (ALT) levels in mice were assessed and the liver maximum tolerated dose (MTD) of ¹⁸⁸Re-HA was determined.

Results

A stable complex of ¹⁸⁸Re-HA was obtained with high radiochemical purity (>90%) and low serum protein binding (2%). Biokinetic studies showed a rapid blood clearance (T_1/2α=21 min). Four hours after administration, ¹⁸⁸Re-HA was almost totally removed from the blood by the liver due to the selective uptake via HA-specific receptors (73.47±5.11% of the injected dose). The liver MTD in mice was 40 Gy after 7.4 MBq of ¹⁸⁸Re-HA injection.

Conclusions

¹⁸⁸Re-HA complex showed good stability, pharmacokinetic and dosimetric characteristics that confirm its potential as a new agent for HCC radiation therapy.     

In vitro binding of 67Ga to isolated rat liver cells

In order to understand the mechanism of the accumulation of gallium citrate (Ga-67) in normal liver, an in vitro investigation system was developed using isolated rat liver cells, and various basal factors relating to ⁶⁷Ga binding to normal rat liver cells were studied. In this study, the values of ⁶⁷Ga binding to the liver cells increased in parallel with the number of cells; however, binding was hardly affected by higher doses of ⁶⁷Ga. The binding of ⁶⁷Ga to the cells was inhibited by the presence of ethylenediaminetetraacetate (EDTA) and citrate. Phosphate and bicarbonate (10^-2 M) slightly inhibited ⁶⁷Ga binding to the cells. The binding of ⁶⁷Ga to the cells increased as the pH was decreased. These results suggest that ⁶⁷Ga binding to normal rat liver cells may occur in free gallium. Moreover, the utilization of isolated rat liver cells is useful for understanding the ⁶⁷Ga accumulation mechanism in normal liver.     

Molecular imaging of cholinergic processes in prostate cancer using <Superscript>11</Superscript>C-donepezil and <Superscript>18</Superscript>F-FEOBV

Purpose

High-grade prostate cancer (PC) displays parasympathetic neoneurogenesis. We investigated the binding of two PET tracers that visualize cholinergic nerves in PC tissue using autoradiography.

Methods

Prostatectomy tissue was subjected to autoradiography with ¹¹C-donepezil and ¹⁸F-FEOBV and correlated with Gleason scores (GS). Regions of interest on the autoradiograms were defined and quantified. Tracer binding in cancer tissue regions was compared with that in normal tissue.

Results

We included 13 patients with biopsy-verified PC. In particular, ¹¹C-donepezil uptake was higher in “high-grade” PC (GS ≥4?+?3) than in “low-grade” PC and benign hyperplasia. ¹¹C-donepezil uptake ranged from a mean of 56 % higher (GS 3?+?3) to 409 % higher (GS 4?+?4), and ¹⁸F-FEOBV uptake ranged from 67 % higher (GS 3?+?3) to 194 % higher (GS 4?+?5). The uptake of both tracers was higher in PC with a high GS than in PC with a low GS, but the difference was significant only for ¹¹C-donepezil (p?=?0.003).

Conclusion

Uptake of PET tracers binding to cholinergic nerves was markedly higher in PC with a high GS than in PC with a low GS. This finding implies that ¹¹C-donepezil PET/CT may be able to differentiate between low-grade and high-grade PC.

     

<Superscript>68</Superscript>Ga-labelled DOTA-derivatised peptide ligands

⁶⁸Ge/⁶⁸Ga generators provide cyclotron-independent access to positron emission tomography (PET) radiopharmaceuticals. We describe a system which allows the safe and efficient handling of ⁶⁸Ge/⁶⁸Ga generator eluates for labelling of DOTA-derivatised peptide ligands. The system comprises concentration and purification of the ⁶⁸Ga eluate as well as labelling and purification steps for peptides, and can be used with different ⁶⁸Ge/⁶⁸Ga generator types. The suitability and efficiency were tested with two different DOTA-derivatised somatostatin derivatives and a DOTA-derivatised bombesin derivative. Amounts of 10–20 nmol of the peptides were sufficient and resulted in labelling yields of 50% for all peptides. The built-in safety precautions have proven to be appropriate in allowing use of the method for routine clinical applications. The system was set up and operated in a hot lab by personnel with no previous experience in the preparation of PET radiopharmaceuticals.     

Measuring SSRI occupancy of SERT using the novel tracer [123I]ADAM: a SPECT validation study

Purpose Serotonergic brain regions play a crucial role in the modulation of emotion, and serotonergic dysfunction may contribute to several neurological disorders. [¹²³I]ADAM is a novel SPECT tracer which binds with high affinity to serotonin transporters (SERT). The objective of this study was to compare different methods for the quantification of tracer binding and to develop a simplified single-scan protocol for this tracer, as well as to investigate its potential for characterisation of the transporter occupancy versus plasma concentration curve of a selective serotonin re-uptake inhibitor (SSRI).Methods Dynamic SPECT scans were performed on 16 healthy volunteers after administration of 150 MBq [¹²³I]ADAM. Data were acquired from the time of injection until 5.5 h after injection in 30- or 45-min sessions. Each subject was scanned twice: with and without pre-treatment with the SSRI citalopram in various dosage regimens. The plasma concentration of citalopram (C_p) was determined from venous samples. Images were reconstructed by filtered back-projection with scatter and attenuation correction. Tracer binding was quantified for midbrain, striatum and thalamus using cerebellum as a reference region. Quantification was done by kinetic modelling, graphical analysis and multi-linear regression, as well as by the ratio method, with binding potential (BP₂) as the outcome measure. The SERT occupancy by citalopram was determined relative to the baseline scan for each subject, and the occupancy versus C_p curve was fitted with the E_max model.Results The highest binding of [¹²³I]ADAM was in midbrain (mean baseline BP₂±SD=1.31±0.29), with lower binding in thalamus (0.79±0.16) and striatum (0.66±0.13). There was good agreement between BP₂ values obtained by different quantification methods. Using the ratio method, the best agreement with kinetic modelling was obtained with data from the time interval [200,260] min after injection. The fitting of the midbrain occupancy curve yielded a maximum occupancy of 84% and a plasma concentration required to reach 50% of the maximum of 2.5 ng/ml, with a goodness-of-fit variability of 13% (SD).Conclusion Binding of [¹²³I]ADAM to SERT in midbrain can be quantified with a single scan starting 200 min after injection. However, the variability of estimated occupancy values may be too high for critical assessment of occupancy of SERT by SSRI.     

[123I]Iodobenzamide binding to the rat dopamine D2 receptor in competition with haloperidol and endogenous dopamine—an in vivo imaging study with a dedicated small animal SPECT

Purpose This study assessed [¹²³I]iodobenzamide binding to the rat dopamine D₂ receptor in competition with haloperidol and endogenous dopamine using a high-resolution small animal SPECT.Methods Subsequent to baseline quantifications of D₂ receptor binding, imaging studies were performed on the same animals after pre-treatment with haloperidol and methylphenidate, which block D₂ receptors and dopamine transporters, respectively.Results Striatal baseline equilibrium ratios (V₃) of [¹²³I]iodobenzamide binding were 1.42±0.31 (mean±SD). After pre-treatment with haloperidol and methylphenidate, V₃ values decreased to 0.54±0.46 (p<0.0001) and 0.98±0.48 (p=0.009), respectively.Conclusion The decrease in [¹²³I]iodobenzamide binding induced by pre-treatment with haloperidol reflects D₂ receptor blockade, whereas the decrease in receptor binding induced by pre-treatment with methylphenidate can be interpreted in terms of competition between [¹²³I]IBZM and endogenous dopamine. Findings show that multiple in vivo measurements of [¹²³I]iodobenzamide binding to D₂ receptors in competition with exogenous and endogenous ligands are feasible in the same animal. This may be of future relevance for the in vivo evaluation of novel radioligands as well as for studying the interrelations between pre- and/or postsynaptic radioligand binding and different levels of endogenous dopamine.     

Repeated injections of 131I-rituximab show patient-specific stable biodistribution and tissue kinetics

Purpose It is generally assumed that the biodistribution and pharmacokinetics of radiolabelled antibodies remain similar between dosimetric and therapeutic injections in radioimmunotherapy. However, circulation half-lives of unlabelled rituximab have been reported to increase progressively after the weekly injections of standard therapy doses. The aim of this study was to evaluate the evolution of the pharmacokinetics of repeated ¹³¹I-rituximab injections during treatment with unlabelled rituximab in patients with non-Hodgkins lymphoma (NHL).Methods Patients received standard weekly therapy with rituximab (375 mg/m²) for 4 weeks and a fifth injection at 7 or 8 weeks. Each patient had three additional injections of 185 MBq ¹³¹I-rituximab in either treatment weeks 1, 3 and 7 (two patients) or weeks 2, 4 and 8 (two patients). The 12 radiolabelled antibody injections were followed by three whole-body (WB) scintigraphic studies during 1 week and blood sampling on the same occasions. Additional WB scans were performed after 2 and 4 weeks post ¹³¹I-rituximab injection prior to the second and third injections, respectively.Results A single exponential radioactivity decrease for WB, liver, spleen, kidneys and heart was observed. Biodistribution and half-lives were patient specific, and without significant change after the second or third injection compared with the first one. Blood T_1/2, calculated from the sequential blood samples and fitted to a bi-exponential curve, was similar to the T_1/2 of heart and liver but shorter than that of WB and kidneys. Effective radiation dose calculated from attenuation-corrected WB scans and blood using Mirdose3.1 was 0.53+0.05 mSv/MBq (range 0.48–0.59 mSv/MBq). Radiation dose was highest for spleen and kidneys, followed by heart and liver.Conclusion These results show that the biodistribution and tissue kinetics of ¹³¹I-rituximab, while specific to each patient, remained constant during unlabelled antibody therapy. RIT radiation doses can therefore be reliably extrapolated from a preceding dosimetry study.     

Biological behavior of 67Ga-citrate in New Zealand White rabbits

The pharmacokinetics, protein binding, excretion and tissue distribution of ⁶⁷Ga after the administration of ⁶⁷Ga-citrate to New Zealand White rabbits is described. Data for ⁶⁷Ga blood levels were best described by an equation with three exponential components exhibiting half lives of 0.25 h, 7.4 h and 19.5 h, with almost all of the activity in a protein bound form. Weekly urinary excretion ( 27%), possibly in a metabolized form, and fecal elimination (20%) were greater than the reported values in man, but there was a similar organ distribution pattern in these animals as in man. The overall biological handling was judged to be similar in both species making the rabbit a suitable model for further ⁶⁷Ga-citrate studies in vivo.     

Role of 11C-choline PET/CT in the re-staging of prostate cancer patients with biochemical relapse and negative results at bone scintigraphy

Aim

to evaluate the utility of ¹¹C-choline PET/CT in prostate cancer (PC) patients who have demonstrated a biochemical recurrence and a negative bone scintigraphy (BS).

Materials and methods

123 consecutive PC patients (mean age 67.6 years; range 54–83) with a biochemical relapse (mean PSA value 3.3 ng/mL; range 0.2–25.5) after radical prostatectomy (RP) were included in our retrospective study. Patients underwent a BS that resulted negative and a ¹¹C-choline PET/CT within 4 months from BS (range: 1 day to 4 months; mean: 2.5 months). Validation of results was established by: (1) a positive biopsy, (2) a positive subsequent BS, CT or MR and (3) a normalization of ¹¹C-choline uptake after systemic therapy or a progression of the disease.

Results

¹¹C-choline PET/CT was positive in 42/123 patients (34.1%). ¹¹C-choline PET/CT detected lesions in: bone (10 patients), lymph-nodes (20 patients), bone and lymph nodes (7 patients), bone and lung (1 patient), lymph-nodes and lung (1 patient), local relapse (3 patients). Overall, ¹¹C-choline PET/CT showed a total of 30 unknown bone lesions in 18/123 (14.6%) patients.

Conclusion

¹¹C-choline PET/CT showed a better sensitivity than BS in patients with biochemical relapse after RP: ¹¹C-choline PET/CT detected unknown bone lesions in 18/123 (14.6%) patients.     

Scintigraphic evaluation of liver transplant function

Since the initiation of liver transplantation at our institution 9 yr ago, 73 patients ranging in age from 8 mo to 64 yr have undergone this procedure. In the immediate postoperative period and at various times thereafter as deemed necessary, radionuclide studies were performed using one of the iminodiacetic acid (IDA) derivatives labeled with 99mTc. Initially, these studies were performed using labeled PIPIDA with a shift to diisopropyl IDA when this latter agent became available. The IDA agent is administered as a bolus so that the "flow" and "pooling" may be viewed immediately after injection. This is followed by sequential imaging at various times up to 24 hr, with optional graphic tracings of hepatic and bowel patterns of uptake and clearance of radioactivity. An analysis of the initial portion of the IDA scan yields useful information regarding the arterial and portal venous supply of the liver. The rapidity of hepatic concentration and excretion provides a direct measure of hepatocyte function which is particularly helpful when used sequentially to follow the response of the liver to therapy for rejection or infection. The study is also used to assess the biliary system for obstruction or leaks.     

Optimal dose of <Superscript>18</Superscript>F-FDG required for whole-body PET using an LSO PET camera

Reducing the acquisition time of whole-body fluorine-18 fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) (corrected for attenuation) is of major importance in clinical practice. With the introduction of lutetium oxyorthosilicate (LSO), the acquisition time can be dramatically reduced, provided that patients are injected with larger amounts of tracer and/or the system is operated in 3D mode. The aim of this study was to determine the optimal dose of ¹⁸F-FDG required in order to achieve good-to-excellent image quality when a "3-min emission, 2-min transmission/bed position" protocol is used for an LSO PET camera. A total of 218 consecutive whole-body ¹⁸F-FDG PET studies were evaluated retrospectively. After excluding patients with liver metastases, hyperglycaemia and paravenous injections, the final study population consisted of 186 subjects (112 men, 74 women, age 59±15 years). Patients were injected with an activity of ¹⁸F-FDG ranging from 2.23 to 15.21 MBq/kg. Whole-body images corrected for attenuation (3 min emission, 2 min transmission/bed position) were acquired with an LSO PET camera (Ecat Accel,Siemens) 60 min after tracer administration. Patients were positioned with their arms along the body. Image reconstruction was done iteratively and a post-reconstruction filter was applied. Image quality was scored visually by two independent observers using a five-point scoring scale (poor, reasonable, good, very good, excellent). In addition, the coefficient of variability (COV) was measured in a region of interest over the liver in order to quantify noise. Of the images obtained in 118 patients injected with 8 MBq/kg ¹⁸F-FDG, 92% and 90% were classified as good, very good or excellent by observer 1 and observer 2, respectively. The COV averaged 10.63%±3.19% for doses 8 MBq/kg and 16.46%±5.14% for doses <8 MBq/kg. Administration of an ¹⁸F-FDG dose of 8 MBq/kg results in images of good to excellent quality in the vast majority of patients when using an LSO PET camera and applying a 3-min emission, 2-min transmission/bed position acquisition protocol. At lower doses, a rapid decline in image quality and increasing noise are observed. Alternative protocols should be adopted in order to compensate for the loss in image quality when doses <8 MBq/kg are used.     

Quantitation of dopamine transporter blockade by methylphenidate: first in vivo investigation using [123I]FP-CIT and a dedicated small animal SPECT

Purpose The aim of this study was to investigate the feasibility of assessing dopamine transporter binding after treatment with methylphenidate in the rat using a recently developed high-resolution small animal single-photon emission computed tomograph (TierSPECT) and [¹²³I]FP-CIT.Methods [¹²³I]FP-CIT was administered intravenously 1 h after intraperitoneal injection of methylphenidate (10 mg/kg) or vehicle. Animals underwent scanning 2 h after radioligand administration. The striatum was identified by superimposition of [¹²³I]FP-CIT scans with bone metabolism and perfusion scans obtained with ^99mTc-DPD and ^99mTc-tetrofosmin, respectively. As these tracers do not pass the blood–brain barrier, their distribution permits the identification of extracerebral anatomical landmarks such as the orbitae and the harderian glands. The cerebellum was identified by superimposing [¹²³I]FP-CIT scans with images of brain perfusion obtained with ^99mTc-HMPAO.Results Methylphenidate-treated animals and vehicle-treated animals yielded striatal equilibrium ratios (V₃) of 0.24±0.26 (mean ± SD) and 1.09±0.42, respectively (t test, two-tailed, p<0.0001). Cortical V₃ values amounted to 0.05±0.28 (methylphenidate) and 0.3±0.39 (saline, p=0.176). This first in vivo study of rat dopamine transporter binding after pre-treatment with methylphenidate showed a mean reduction of 78% in striatal [¹²³I]FP-CIT accumulation.Conclusion The results can be interpreted in terms of a pharmacological blockade in the rat striatum and show that in vivo quantitation of dopamine transporter binding is feasible with [¹²³I]FP-CIT and the TierSPECT. This may be of future relevance for in vivo investigations on rat models of attention deficit/hyperactivity disorder. Furthermore, our findings suggest that investigations in other animal models, e.g. of Parkinsons and Huntingtons disease, may be feasible using SPECT radioligands and small animal imaging systems.     

A useful EGFR-TK ligand for tumor diagnosis with SPECT: development of radioiodinated 6-(3-morpholinopropoxy)-7-ethoxy-4-(3′-iodophenoxy)quinazoline

Objective

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) represents an attractive target for tumor diagnosis agents. Previously, radioiodinated 4-(3-iodophenoxy)-6,7-diethoxyquinazoline (PHY) was reported to possess good characteristics as a tumor imaging agent. We have explored the feasibility of developing tumor diagnosis ligands superior to radioiodinated PHY.

Methods

New phenoxyquinazoline derivatives were designed with various side chains introduced to the 6th position of PHY. The IC₅₀ values of the new derivatives to interrupt EGFR-TK phosphorylation were evaluated and compared to well-known EGFR-TK inhibitors. Tumor uptake studies of the new ¹²⁵I-labeled derivatives were conducted with A431 tumor-bearing mice. Selectivity and binding characteristics were analyzed by in vitro blocking studies and a binding assay. Furthermore, SPECT/CT scans were performed using A431 tumor-bearing mice.

Results

Six quinazoline derivatives were designed and synthesized, and among these, 6a–d were found to have relatively high EGFR-TK inhibitory potency. In tumor uptake studies, [¹²⁵I]6a ([¹²⁵I]PYK) was found to have the highest tumor uptake and longest retention in tumors. In contrast, [¹²⁵I]PYK was rapidly cleared from peripheral tissues, resulting in a high tumor-to-tissue ratio 24 h after injection. Moreover, the EGFR-TK selectivity of [¹²⁵I]PYK was confirmed by pretreatment experiments with specific EGFR-TK inhibitors. Furthermore, [¹²⁵I]PYK provided clear SPECT images of tumors.

Conclusions

Radioiodinated PYK, one of the newly synthesized quinazoline derivatives, was found to be a desirable ligand for EGFR-TK SPECT imaging. [¹²⁵I]PYK showed high tumor accumulation and selective EGFR-TK binding and also succeeded in delivering high contrast imaging of tumors. These favorable characteristics of [¹²⁵I]PYK suggest that the ¹²³I-labeled counterpart, [¹²³I]PYK, would have great potential for diagnostic SPECT tumor imaging.     

Technetium Tc 99m plasmin in the diagnosis of inflammatory disease

The localization characteristics of technetium Tc 99m plasmin were studied in experimental animals to investigate the use of^99mTc-plasmin for imaging inflammatory processes. At various times after abscess induction using turpentine in rats, the in vivo distribution properties of^99mTc-plasmin, gallium citrate Ga 67,¹²⁵I-fibrinogen, and^99mTc-human serum albumin (HSA) were studied by gamma-camera imaging. The in vivo binding of each radiopharmaceutical was also tested in rat and human plasma clots. Region-of-interest analyses of gamma-camera images showed relatively poor^99mTc-plasmin localization at sites of abscess formation. The ratio of abscess-to-control activity of this radiopharmaceutical did not exceed that of⁶⁷Ga,¹²⁵I-fibrinogen, or^99mTc-HSA. In vitro assays of each of the radiopharmaceuticals in plasma clots showed^99mTc-phasmin and¹²⁵I-fibrinogen to have the best localization characteristics.     

Simultaneous whole-body <Superscript>18</Superscript>F–PSMA-1007-PET/MRI with integrated high-resolution multiparametric imaging of the prostatic fossa for comprehensive oncological staging of patients with prostate cancer: a pilot study

Introduction

The aim of the present study was to explore the clinical feasibility and reproducibility of a comprehensive whole-body ¹⁸F–PSMA-1007-PET/MRI protocol for imaging prostate cancer (PC) patients.

Methods

Eight patients with high-risk biopsy-proven PC underwent a whole-body PET/MRI (3 h p.i.) including a multi-parametric prostate MRI after ¹⁸F–PSMA-1007-PET/CT (1 h p.i.) which served as reference. Seven patients presented with non-treated PC, whereas one patient presented with biochemical recurrence. SUV_mean-quantification was performed using a 3D–isocontour volume-of-interest. Imaging data was consulted for TNM-staging and compared with histopathology. PC was confirmed in 4/7 patients additionally by histopathology after surgery. PET-artifacts, co-registration of pelvic PET/MRI and MRI-data were assessed (PI-RADS 2.0).

Results

The examinations were well accepted by patients and comprised 1 h. SUV_mean-values between PET/CT (1 h p.i.) and PET/MRI (3 h p.i.) were significantly correlated (p < 0.0001, respectively) and similar to literature of ¹⁸F–PSMA-1007-PET/CT 1 h vs 3 h p.i. The dominant intraprostatic lesion could be detected in all seven patients in both PET and MRI. T2c, T3a, T3b and T4 features were detected complimentarily by PET and MRI in five patients. PET/MRI demonstrated moderate photopenic PET-artifacts surrounding liver and kidneys representing high-contrast areas, no PET-artifacts were observed for PET/CT. Simultaneous PET-readout during prostate MRI achieved optimal co-registration results.

Conclusions

The presented ¹⁸F–PSMA-1007-PET/MRI protocol combines efficient whole-body assessment with high-resolution co-registered PET/MRI of the prostatic fossa for comprehensive oncological staging of patients with PC.

     

Technetium coordination state as a factor of stability in 99mTc-complexes used in hepatobiliary system: Comparative studies on 99mTc-complexes of pyridoxal with glutamate (Tc-PG) and isoleucine (Tc-PI)

Studies on ^99mTc-Penicillamine (Tc-Pen) have given us some insight into the significance of the technetium coordination state in hepatobiliary clearance behavior.A ^99mTc-complex of pyridoxal and glutamate (Tc-PG) prepared by Baker et al. (1975) using an autoclaving process or by a Sn-Resin kit method (Horiuchi 1981) was compared with a ^99mTc-complex of pyridoxal and isoleucine (Tc-PI) prepared by the method of Kato and Hazue (1978) through an intermediate compound of stannous ion, at room temperature.Tc-PG and TcPI complexes analyzed by thin layer chromatography, sephadex column chromatography (G-15), octanol extraction, and ligand exchange reaction showed different chemical properties. Their biological evaluation also demonstrated great differences in biodistribution in mice, metabolic studies, protein binding, and rat bile excretion.Tc-PG was estimated as an hepatobiliary agent with strong metal-ligand binding, inert to ligand exchange reaction with Pen at physiological pH; the likely occurrence of technetium in a mononuclear or dinuclear state providing the great stability observed in its biological and in vivo behavior was compared with the relatively weaker binding observed in Tc-PI, a highly lipophilic complex of high liver partition but of low stability, denoting its different chemical characteristics.The technetium coordination state in radiopharmaceuticals is responsible for the integrity of the molecule while in the blood pool and its relevance in impaired liver uptake is discussed.     

Dopamine transporter density of basal ganglia assessed with [<Superscript>123</Superscript>I]IPT SPET in obsessive-compulsive disorder

It has been suggested that dopamine, as well as serotonin, is associated with the pathophysiology of obsessive-compulsive disorder (OCD). Thus, many studies have been performed on brain regions associated with dopamine in patients with OCD. In the present study, we investigated the DAT density of the basal ganglia using iodine-123 labelled N-(3-iodopropen-2-yl)-2-carbomethoxy-3-(4-chlorophenyl) tropane ([¹²³I]IPT) single-photon emission tomography (SPET) and evaluated the activity of the presynaptic dopamine function in patients with OCD. Fifteen patients with OCD and 19 normal control adults were included in the study. We performed brain SPET 2 h after the intravenous administration of [¹²³I]IPT and carried out both quantitative and qualitative analyses using the obtained SPET data, which were reconstructed for the assessment of the specific/non-specific dopamine transporter (DAT) binding ratio in the basal ganglia. We then investigated the correlation between the severity scores of OCD symptoms assessed with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the specific/non-specific DAT binding ratio of the basal ganglia. Compared with normal control adults, patients with OCD showed a significantly increased specific/non-specific DAT binding ratio in the right basal ganglia and a tendency towards an increased specific/non-specific DAT binding ratio in the left basal ganglia. No significant correlation was found between the total scores on the Y-BOCS and the specific/non-specific DAT binding ratio of the basal ganglia. These findings suggest that the dopaminergic neurotransmitter system of the basal ganglia in patients with OCD could be involved in the pathophysiology of OCD.     

The effect of lipophilicity on the hepatobiliary properties of iminodiacetic acid derivatives in the conditions of hyperbilirubinemia

The partition coefficients (log P) of theoretically possible alkyliodinated iminodiacetic acid (IDA) derivatives and commercial IDA derivatives were calculated using two computer programs: ChemSketch Log P and ChemOffice Ultra. Newly synthesized ligands (DIETHYLIODIDA and DIISOPROPYLIODIDA) with the highest calculated log P were labeled with technetium-99m. The biodistribution and the influence of bilirubin on their biokinetics were investigated in rats and compared to corresponding results for commercial ^99mTc-BROMIDA. Log P of ^99mTc-complexes of synthesized ligands were determined experimentally as well as the protein binding. In comparison to ^99mTc-BROMIDA, ^99mTc-DIETHYLIODIDA has: (a) better biliary excretion (2.76±0.15%ID/g versus 1.83±0.10%ID/g); (b) faster hepatic clearance (2.90±0.21%ID/g versus 7.47±0.70%ID/g) and decreased biliary excretion (for 14% versus 22%) in conditions of hyperbilirubinemia after 15 min. It is proved that ^99mTc-DIISOPROPYLIODIDA has a prolonged hepatic transit time and decreased biliary excretion.     

Can technetium 99m bisdiethylphosphinoethanebis-t butylisocyanide (99mTc-DEPIC) be used for routine radionuclide ventriculography?

Radionuclide ventriculography is a useful investigation in the evaluation of cardiac function. Generally, in vivo technetium 99m-labelled red blood cells (RBC) yield good quality images in ventriculography. However, it is widely believed that some drugs have an adverse effect on RBC labelling. Zanelli et al. (1987) developed a radiopharmaceutical (technetium 99m bisdiethylphosphinoethanebis-t-butylisocyanide,^99mTc-DEPIC) to obtain better results in patients using such drugs. We untertook a prospective study of 6 patients with cardiovascular and/or pulmonary disease using several kinds of drugs to evaluate imaging of the cardiac blood pool with^99mTc-DEPIC and in vivo labelled^99mTc-RBC. After injection, blood samples were taken, and gated equilibrium blood pool studies were performed. The radiochemical purity of the injected^99mTc-DEPIC varied from 76.4 to 93.6% (mean 86.4%, SD 5.7%). The protein (pre-albumin) binding was 100%. Biological half-life in blood varied from 3.3 to 4.7 h (mean 4.1 h, SD 0.5 h). For^99mTc-RBC no significant blood disappearance was seen for 8 h. The percentage of RBC-bound^99mTc varied from 96.9% to 98.3% (mean 97.0%, SD 0.5%) and was stable for at least 8 h. The heart-to-lung, heart-to-spleen, and heart-to-liver ratios were higher for^99mTc-RBC than for^99mTc-DEPIC. Furthermore,^99mTc-DEPIC showed a significant decline of the ejection fraction with time. Visually, the images with^99mTc-RBC were superior to those with^99mTc-DEPIC, especially a few hours after injection. According to our findings, in vivo labelling of^99mTc-RBC is still the method of choice for routine radionuclide ventriculography. The decline of the ejection fraction, the short blood half-life, and the intense liver uptake make^99mTc-DEPIC less suitable for this purpose.