[en] The d,1- and meso-isomers of hexamethylpropyleneamine oxime (HM-PAO) can react with the pentavalent Tc-99m to give lipophilic complexes in which only the d,1-complex can be consistently retained in the brain. In order to get a better understanding about the Tc-99m HM-PAO retention mechanism in the brain, an in-vitro complexation study was carried out on the reduced Tc-99m species with HM-PAO at pH 7.0 and 37.0±0.2 deg C in the presence of glutathione at its brain-level concentration by means of radio-thin layer chromatography and paper electrophoresis. Both of the HM-PAO complexes as well as reduced Tc-99m species could react with the reduced form of glutathione to generate primarily negative charged species which were identified by paper electrophoresis . The d,1-HM-PAO complex was converted immediately, whereas the conversion rate for the meso-isomer complex was slower (Kd = 9.6 x 10^-3 min^-1) at 1 mM of glutathione concentration. The results indicate that the Tc-99m d,1-HM-PAO complex has longer brain-retention time than that of meso-isomer in their biodistribution studies. 10 refs., 5 figs

[en] This study aims to investigate the relationship between the determination of dopamine level by high performance liquid chromatography (HPLC) with electrochemical detection (ECD) and the detection of dopamine transporter (DAT) counts using autoradiography with DAT image agent [^99mTc]TRODAT-1. For striatal lesions, pretreatment of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle shows that autoradiogaphic labeling of striatum region is reduced to near-background level. Using HPLC with ECD, unilateral 6-OHDA treatment is associated with significant (p<0.0002) reductions of dopamine levels. For the striatum of the 6-OHDA-lesioned side, dopamine content and DAT counts are reduced to 97% and 90%, respectively. Thus, our observation indicates a potential of using [^99mTc]TRODAT-1 for the evaluation of animal DAT

[en] A radiopharmaceutical, ¹²³I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([¹²³I]ADAM), has been developed recently for evaluation of how serotonin transporters (SERT) function in the brain. However, the detailed biodistribution and specific binding in certain brain areas are not well investigated. In this study, both phosphor plate imaging and microautoradiography were applied to explore the binding characteristics of [¹²³I]ADAM in SERT neurons. The effect of two psychotropics and one narcotic on the binding of [¹²³I]ADAM to SERT was also studied. Fluoxetine and desipramine, both are psychotropics and specific SERT ligands and decreased the affinity of [¹²³I]ADAM, while p-chloroamphetamine (PCA), a narcotic, destroyed most of serotonergic neurons, as well as reducing the concentration of serotonin and the number of SERT in the brain as shown by the biodistribution of [¹²³I]ADAM. Significant and selective accumulation of [¹²³I]ADAM in the areas from midbrain to brain stem in normal mice with maximum target-to-background ratio was found at 90 minutes postinjection. A rapid clearance of [¹³¹I]ADAM at 120 minutes postinjection was found in the CA1, CA3 and ThN brain areas. In addition, the inhibition effect on binding ability of [¹²³I]ADAM to SERT by the psychotropics and the narcotic was found to have the order of: PCA > fluoxetine > desipramine

[en] Introduction: In locations that lack nearby cyclotron facilities for radionuclide production, generator-based ⁶⁸Ga radiopharmaceuticals might have clinical utility for positron emission tomography (PET) studies of myocardial perfusion and other physiological processes. Methods: The lipophilic and monocationic ⁶⁷Ga-labeled gallium chelates of five novel hexadentate bis(salicylaldimine) ligands the bis(salicylaldimine), bis(3-methoxysalicylaldimine), bis(4-methoxysalicylaldimine), bis(6-meth,oxysalicylaldimine), and bis(4,6-dimethoxysalicylaldimine) of N,N'-bis(3-aminopropyl)-N,N'-dimethylethylenediamine (BAPDMEN), were prepared. The structure of the unlabeled [Ga(4-MeOsal)₂BAPDMEN]⁺PF₆^- salt was determined by X-ray crystallography, and the biodistribution of each of the ⁶⁷Ga-labeled gallium chelates was determined in rats following intravenous administration and compared with the biodistribution of [⁸⁶Rb]rubidium chloride. Results: The [Ga(4-MeOsal)₂BAPDMEN]⁺PF₆^- complex exhibited the expected pseudo-octahedral N₄O₂^2- coordination sphere about the Ga³⁺ center with a trans disposition of the phenolate oxygen atoms. All five ⁶⁷Ga radiopharmaceuticals were found to afford the desired myocardial retention of the radiogallium. The [^67/68Ga][Ga(3-MeOsal)₂BAPDMEN]¹⁺ radiopharmaceutical appears to have the best properties for myocardial imaging, exhibiting 2% of the injected dose in the heart 1 min and 2 h postinjection and very high heart/nontarget ratios (heart/blood ratios of 7.6±1.0 and 54±10 at 1 and 120 min, respectively; heart/liver ratios of 1.8±0.4 and 39±3 at 1 and 120 min, respectively). Conclusions: Most of these new agents, particularly [^67/68Ga][Ga(3-MeOsal)₂BAPDMEN]¹⁺, would appear superior to previously reported bis(salicylaldimine) ligands of N,N'-bis(3-aminopropyl)ethylenediamine as candidates for PET imaging of the heart with ⁶⁸Ga

[en] Background: A novel radioiodine ligand [¹²³I] ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) has been suggested as a promising serotonin transporter (SERT) imaging agent for the central nervous system. In this study, the biodistribution of SERTs in the rabbit brain was investigated using [¹²³I] ADAM and mapping images of the same animal produced by both single-photon emission computed tomography (SPECT) and microautoradiography. A semiquantification method was adopted to deduce the optimum time for SPECT imaging, whereas the input for a simple fully quantitative tracer kinetic model was provided from arterial blood sampling data. Methods: SPECT imaging was performed on female rabbits postinjection of 185 MBq [¹²³I] ADAM. The time-activity curve obtained from the SPECT images was used to quantify the SERTs, for which the binding potential was calculated from the kinetic modeling of [¹²³I] ADAM. The kinetic data were analyzed by the nonlinear least squares method. The effects of the selective serotonin reuptake inhibitors fluoxetine and p-chloroamphetamine (PCA) on rabbits were also evaluated. After scanning, the same animal was sacrificed and the brain was removed for microautoradiography. Regions-of-interest were analyzed using both SPECT and microautoradiography images. The SPECT images were coregistered manually with the corresponding microautoradiography images for comparative study. Results: During the time interval 90-100 min postinjection, the peak specific binding levels in different brain regions were compared and the brain stem was shown to have the highest activity. The target-to-background ratio was 1.89±0.02. Similar studies with fluoxetine and PCA showed a background level for SERT occupation. Microautoradiography demonstrated a higher level of anatomical details of the [¹²³I] ADAM distribution than that obtained by SPECT imaging of the rabbit brain. Conclusion: SPECT imaging of the rabbit brain with [¹²³I] ADAM showed high affinity, high specificity, and favorable kinetics. The time-activity curve showed that the accumulation of the [¹²³I] ADAM in the brain stem reached a maximum between 90 and 100 min postinjection. The microautoradiography provides high-resolution images of the rabbit brain. Our results for the [¹²³I] ADAM biodistribution in the rabbit brains demonstrate that this new radioligand is suitable as a selective SPECT imaging agent for SERTs

[en] In the past 10 years, significant progress has been made in using a technetium-99m dopamine transporter imaging agent, [^99mTc]TRODAT, for routine clinical studies. Developing a molecular imaging agent from bench to the bedside is more than a simple scientific venture. Currently, Taiwan is the only place where [^99mTc]TRODAT is approved for routine clinical use in the diagnosis of Parkinson's disease. The trials and tribulations of developing [^99mTc]TRODAT for routine clinical use in Taiwan provide an interesting case study in how to (critics may say, how not to) develop a molecular imaging agent

[en] The vesicular monoamine transporter type 2 (VMAT2) is highly expressed in pancreatic β-cells and thus has been proposed to be a potential target for measuring β-cell mass (BCM) by molecular imaging. C-11- and F-18-labeled tetrabenazine derivatives targeting VMAT2 have shown some promising results as potential biomarkers for BCM. In the present study, we examined the binding characteristics of 9-fluoropropyl-(+)-dihydrotetrabenzazine ([¹⁸F]AV-133), a potential PET tracer for BCM imaging, in rat pancreas and rat brain. Methods: Pancreatic exocrine cells and pancreatic islet cells were isolated and purified from Sprague-Dawley rats. Membrane homogenates, prepared from both pancreatic exocrine and islet cells as well as from brain striatum and hypothalamus regions, were used for in vitro binding studies. In vitro and ex vivo autoradiography studies with [¹⁸F]AV-133 were performed on rat brain and rat pancreas sections. Immunohistochemistry studies were performed to confirm the distribution of VMAT2 on islet β-cells. Results: Excellent binding affinities of [¹⁸F]AV-133 were observed in rat striatum and hypothalamus homogenates with K_d values of 0.19 and 0.25 nM, respectively. In contrast to single-site binding observed in rat striatum homogenates, rat islet cell homogenates showed two saturable binding sites (site A: K_d=6.76 nM, B_max=60 fmol/mg protein; site B: K_d=241 nM, B_max=1500 fmol/mg protein). Rat exocrine pancreas homogenates showed only a single low-affinity binding site (K_d=209 nM), which was similar to site B in islet cells. In vitro autoradiography of [¹⁸F]AV-133 using frozen sections of rat pancreas showed specific labeling of islets, as evidenced by co-localization with anti-insulin antibody. Ex vivo VMAT2 pancreatic autoradiography in the rat, however, was not successful, in contrast to the excellent ex vivo autoradiography of VMAT2 binding sites in the brain. In vivo/ex vivo islet labeling may be complicated by the presence of the low-affinity/high-capacity site B binding in rat pancreas. Conclusions: [¹⁸F]AV-133 is an excellent imaging agent for mapping VMAT2 sites in rat brain and specifically binds rat islet cells in vitro and postmortem. Additional optimization may be required to achieve ex vivo islet β-cell labeling in rats.

[en] Purpose: The compound (E)-4-(2-(6-(2-(2-(2-¹⁸F-fluoroethoxy)ethoxy)ethoxy) pyridin-3-yl)vinyl)-N-methylbenzenamine ([¹⁸F]AV-45) is a novel radiopharmaceutical capable of selectively binding to β-amyloid (Aβ) plaques. This pilot study reports the safety, biodistribution, and radiation dosimetry of [¹⁸F]AV-45 in human subjects. Methods: In vitro autoradiography and fluorescent staining of postmortem brain tissue from patients with Alzheimer's disease (AD) and cognitively healthy subjects were performed to assess the specificity of the tracer. Biodistribution was assessed in three healthy elderly subjects (mean age: 60.0±5.2 years) who underwent 3-h whole-body positron emission tomography (PET)/computed tomographic (CT) scans after a bolus injection of 381.9±13.9 MBq of [¹⁸F]AV-45. Another six subjects (three AD patients and three healthy controls, mean age: 67.7±13.6 years) underwent brain PET studies. Source organs were delineated on PET/CT. All subjects underwent magnetic resonance imaging (MRI) for obtaining structural information. Results: In vitro autoradiography revealed exquisitely high specific binding of [¹⁸F]AV-45 to postmortem AD brain sections, but not to the control sections. There were no serious adverse events throughout the study period. The peak uptake of the tracer in the brain was 5.12±0.41% of the injected dose. The highest absorbed organ dose was to the gallbladder wall (184.7±78.6 μGy/MBq, 4.8 h voiding interval). The effective dose equivalent and effective dose values for [¹⁸F]AV-45 were 33.8±3.4 μSv/MBq and 19.3±1.3 μSv/MBq, respectively. Conclusion: [¹⁸F]AV-45 binds specifically to Aβ in vitro, and is a safe PET tracer for studying Aβ distribution in human brain. The dosimetry is suitable for clinical and research application.

[en] Introduction: [¹²³I]-2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([¹²³I]ADAM), a novel radiotracer, has promising application in the imaging of the serotonin transporter (SERT) in the human brain. In this study, the optimal scanning time for acquiring brain single photon emission computed tomography (SPECT) images was determined by performing dynamic SPECT studies at intervals from 0 to 6 h postinjection of [¹²³I]ADAM. Additionally, radiation-absorbed doses were determined for three healthy human subjects using attenuation-corrected images. Methods: Twelve subjects were randomized into one of three study groups as follows: whole-body distribution imaging (n=3), dynamic SPECT imaging (n=3) and brain SPECT imaging (n=6). The radiation-absorbed dose was calculated using MIRDOSE 3.0 software with attenuation-corrected data. The specific binding (SB) ratio of the brain stem was measured from dynamic SPECT images to determine the optimal scanning time. Results: Dynamic SPECT images showed that the SB of the brain stem gradually increased to a maximum 4 h postinjection. Single photon emission computed tomography images at 4 h postinjection showed a high uptake of the radiotracer (SB) in the hypothalamus (1.40±0.12), brain stem (1.44±0.16), pons (1.13±0.14) and medial temporal lobe (0.59±0.10). The mean adult male value of effective dose was 3.37x10^-2 mSv/MBq with a 4.8-h urine-voiding interval. Initial high uptake in SERT-rich sites was demonstrated in the lung and brain. A prominent washout of the radiotracer from the lung further increased brain radioactivity that reached a peak value of 5.03% of injected dose 40 min postinjection. Conclusions: [¹²³I]ADAM is a promising radiotracer for SPECT imaging of SERT in humans with acceptable dosimetry and high uptake in SERT-rich regions. Brain SPECT images taken within 4 h following injection show optimal levels of radiotracer uptake in known SERT sites. However, dynamic changes in lung SERT distribution must be carefully evaluated

[en] Aim: Recently, the feasibility of detecting amyloid plaques in the living brain by positron emission tomography (PET) imaging has been successfully demonstrated. As such, imaging β-amyloid (Aβ) plaques in the brain may further advance the differential diagnosis of the disease and allow clinicians to measure the effectiveness of therapeutic drugs aimed at lowering plaques in the brain. We report herein the preclinical validation of a potential ¹⁸F-labeled biphenylalkyne, AV-138, as a preliminary step toward developing the imaging agent for patients suspected of having Alzheimer's disease. Methods: In vitro binding was carried out in the homogenates prepared from postmortem AD brains with [¹²⁵I]IMPY as the radioligand. [¹⁸F]AV-138 was successfully prepared using a tosylate precursor and Sumitomo modules for radiosynthesis. Similarly, specific binding of [¹⁸F]AV-138 (0.02-0.05 nM) to homogenates, prepared from gray and white matters of pooled AD patients and control subjects, was performed. Specific binding to Aβ plaques was measured by autoradiography in AD brain sections (n=11), and the same brain sections were fluorescently stained with thioflavin-S (TF-S). Images of both radiolabeling and fluorescent staining of plaques obtained by a phosphor imager were used for correlation image analysis. Results: As expected, AV-138 displayed a high binding affinity (K_i=2.4±0.7 nM) in AD gray matter homogenates (due to its high level of Aβ plaque accumulation). Specific binding can be clearly measured in the AD gray matter homogenates, but not in the AD white matters. Control brain homogenates, due to a lack of Aβ plaques, also showed no specific binding. Furthermore, in vitro autoradiography of postmortem AD brain sections showed that the high binding signal of [¹⁸F]AV-138 was specifically due to Aβ plaques. Fluorescent staining of plaques with TF-S correlated well with the radiolabeling of [¹⁸F]AV-138 in AD brain sections (r>0.90). Conclusion: Taken together, these preliminary results strongly suggest that [¹⁸F]AV-138 is potentially useful for imaging Aβ plaques in the living human brain.