Dosimetric Analysis of a Phase I Study of PSMA-Targeting Radiopharmaceutical Therapy With 177 LuLudotadipep in Patients With Metastatic Castration-Resistant Prostate Cancer

Objective@#177 Lutetium [Lu] Ludotadipep is a novel prostate-specific membrane antigen targeting therapeutic agent with an albumin motif added to increase uptake in the tumors. We assessed the biodistribution and dosimetry of [ 177 Lu]Ludotadipep in patients with metastatic castration-resistant prostate cancer (mCRPC). @*Materials and Methods@#Data from 25 patients (median age, 73 years; range, 60–90) with mCRPC from a phase I study with activity escalation design of single administration of [ 177 Lu]Ludotadipep (1.85, 2.78, 3.70, 4.63, and 5.55 GBq) were assessed. Activity in the salivary glands, lungs, liver, kidneys, and spleen was estimated from whole-body scan and abdominal SPECT/CT images acquired at 2, 24, 48, 72, and 168 h after administration of [ 177 Lu]Ludotadipep. Red marrow activity was calculated from blood samples obtained at 3, 10, 30, 60, and 180 min, and at 24, 48, and 72 h after administration. Organand tumor-based absorbed dose calculations were performed using IDAC-Dose 2.1. @*Results@#Absorbed dose coefficient (mean ± standard deviation) of normal organs was 1.17 ± 0.81 Gy/GBq for salivary glands, 0.05 ± 0.02 Gy/GBq for lungs, 0.14 ± 0.06 Gy/GBq for liver, 0.77 ± 0.28 Gy/GBq for kidneys, 0.12 ± 0.06 Gy/GBq for spleen, and 0.07 ± 0.02 Gy/GBq for red marrow. The absorbed dose coefficient of the tumors was 10.43 ± 7.77 Gy/GBq. @*Conclusion@#[ 177 Lu]Ludotadipep is expected to be safe at the dose of 3.7 GBq times 6 cycles planned for a phase II clinical trial with kidneys and bone marrow being the critical organs, and shows a high tumor absorbed dose.

Clinical Usefulness of ¹⁸F-FC119S Positron-Emission Tomography as an Auxiliary Diagnostic Method for Dementia: An Open-Label, Single-Dose, Evaluator-Blind Clinical Trial

BACKGROUND@#AND PURPOSE: The aim of this study was to determine the diagnostic performance and safety of a new ¹⁸F-labeled amyloid tracer, ¹⁸F-FC119S.@*METHODS@#This study prospectively recruited 105 participants, comprising 53 with Alzheimer's disease (AD) patients, 16 patients with dementia other than AD (non-AD), and 36 healthy controls (HCs). In the first screening visit, the Seoul Neuropsychological Screening Battery cognitive function test was given to the dementia group, while HC subjects completed the Korean version of the Mini Mental State Examination. Individuals underwent ¹⁸F-FC119S PET, ¹⁸F-fluorodeoxyglucose (FDG) PET, and brain MRI. The diagnostic performance of ¹⁸F-FC119S PET for AD was compared to a historical control (comprising previously reported and currently used amyloid-beta PET agents), ¹⁸F-FDG PET, and MRI. The standardized uptake value (SUV) ratio (ratio of the cerebral cortical SUV to the cerebellar SUV) was measured for each PET data set to provide semiquantitative analysis. All adverse effects during the clinical trial periods were monitored.@*RESULTS@#Visual assessments of the ¹⁸F-FC119S PET data revealed a sensitivity of 92% and a specificity of 84% in detecting AD. ¹⁸F-FC119S PET demonstrated equivalent or better diagnostic performance for AD detection than the historical control, ¹⁸F-FDG PET (sensitivity of 80.0% and specificity of 76.0%), and MRI (sensitivity of 98.0% and specificity of 50.0%). The SUV ratios differed significantly between AD patients and the other groups, at 1.44±0.17 (mean±SD) for AD, 1.24±0.09 for non-AD, and 1.21±0.08 for HC. No clinically significant adverse effects occurred during the trial periods.@*CONCLUSIONS@#¹⁸F-FC119S PET provides high sensitivity and specificity in detecting AD and therefore may be considered a useful diagnostic tool for AD.

Synthesis and Preliminary Evaluation of 9-(4-18FFluoro-3-hydroxymethylbutyl) Guanine (18FFHBG) in HSV1-tk Gene Transduced Hepatoma Cell / 핵의학분자영상

PURPOSE: The HSV1-tk reporter gene system is the most widely used system because of its advantage that direct monitoring is possible without the introduction of a separate reporter gene in case of HSV1-tk suicide gene therapy. In this study, we investigate the usefulness of the reporter probe (substrate), 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG) for non-invasive reporter gene imaging using PET in HSV1-tk expressing hepatoma model. MATERIALS AND METHODS: Radiolabeled FHBG was prepared in 8 steps from a commercially available triester. The labeling reaction was carried out by NCA nucleophilic substitution with K[18F]/K2.2.2. in acetonitrile using N2-monomethoxytrityl-9-[4-(tosyl)-3-monomethoxytritylmethylbutyl]guanine as a precursor, followed by deprotection with 1 N HCl. Preliminary biological properties of the probe were evaluated with MCA cells and MCA-tk cells transduced with HSV1-tk reporter gene. In vitro uptake and release-out studies of [18F]FHBG were performed, and was analyzed correlation between [18F]FHBG uptake ratio according to increasing numeric count of MCA-tk cells and degree of gene expression. MicroPET scan image was obtained with MCA and MCA-tk tumor bearing Balb/c-nude mouse model. RESULTS: [18F]FHBG was purified by reverse phase semi-HPLC system and collected at around 16-18 min. Radiochemical yield was about 20-25% (corrected for decay), radiochemical purity was >95% and specific activity was around >55.5 GBq/micro mol. Specific accumulation of [18F]FHBG was observed in HSV1-tk gene transduced MCA-tk cells but not in MCA cells, and consecutive 1 hour release-out results showed more than 86% of uptaked [18F]FHBG was retained inside of cells. The uptake of [18F]FHBG was showed a highly significant linear correlation (R2=0.995) with increasing percentage of MCA-tk numeric cell count. In microPET scan images, remarkable difference of accumulation was observed for the two type of tumors. CONCLUSION: [18F]FHBG appears to be a useful as non-invasive PET imaging substrate in HSV1-tk expressing hepatoma model.

Dopamine Transporter Density of the Basal Ganglia Assessed with I-123 IPT SPECT in Methamphetamine Abusers / 대한핵의학회잡지

PURPOSE: Functional imaging of dopamine transporter (DAT) defines integrity of the dopaminergic system, and DAT is the target site of drugs of abuse such as cocaine and methamphetamine. Functional imaging the DAT may be a sensitive and selective indicator of neurotoxic change by the drug. The aim of the present study is to evaluate the clinical implications of qualitative/quantitative analyses of dopamine transporter imaging in methamphetamine abusers. MATERIALS AND METHODS: Six detoxified methamphetamine abusers (abuser group) and 4 volunteers (control group) were enrolled in this study. Brain MRI was performed in all of abuser group. Abuser group underwent psychiatric and depression assessment using brief psychiatric rating scale (BPRS) and Hamilton depression rating scale (HAMD), respectively. All of the subjects underwent I-123 IPT SPECT (IPT SPECT). IPT SPECT image was analysed with visual qualitative method and quantitative method using basal ganglia dopamine transporter (DAT) specific/non-specific binding ratio (SBR). Comparison of DAT SBR between abuser and control groups was performed. We also performed correlation tests between psychiatric and depression assessment results and DAT SBR in abuser group. RESULTS: All of abuser group showed normal MRI finding, but had residual psychiatric and depressive symptoms, and psychiatric and depressive symptom scores were exactly correlated (r=1.0, p=0.005) each other. Five of them showed abnormal finding on qualitative visual I-123 IPT SPECT. Abuser group had lower basal ganglia DAT SBR than that of control (2.38+/-0.20 vs 3.04+/-0.27, p=0.000). Psychiatric and depressive symptoms were negatively well correlated with basal ganglia DAT SBR (r=-0.908, p=0.012, r=-0.924, p=0.009). CONCLUSION: These results suggest that dopamine transporter imaging using I-123 IPT SPECT may be used to evaluate dopaminergic system of the basal ganglia and the clinical status in methamphetamine abusers.

Dopamine Transporter Density Assessed with 123IIPT SPECT Before and After Risperidone Treatment in Children with Tourette's Disorder / 대한핵의학회잡지

PURPOSE: Tourette's disorder (TD), which is characterized by multiple waxing and waning motor tics and one or more vocal tics, is known to be associated with abnormalities in the dopaminergic system. To testify our hypothesis that risperidone would improve tic symptoms of TD patients through the change of the dopaminergic system, we measured the dopamine transporter (DAT) densities between drug-naive children with TD and normal children, and investigated the DAT density before and after treatment with risperidone in drug-naive children with TD, using iodine-123 labelled N- (3-iodopropen-2-yl) -2beta-carbomethoxy -3beta- (4-chlorophenyl) tropane ([123I]IPT) single photon emission computed tomography (SPECT). MATERIALS AND METHODS: [123I]IPT SPECT imaging and Yale Global Tic Severity Scale-Korean version (YGTSS-K) for assessing the tic symptom severity were carried out before and after treatment with risperidone for 8 weeks in nine drug-naive children with TD. Eleven normal children also underwent SPECT imaging 2 hours after an intravenous administration of [123I]IPT. RESULTS: Drug-naive children with TD had a significantly greater increase in the specific/nonspecific DAT binding ratio of both basal ganglia compared with the normal children. However, no significant difference in the specific/nonspecific DAT binding ratio of the basal ganglia before and after treatment with risperidone in children with TD was found, although tic symptoms were significantly improved with risperidone. CONCLUSION: These findings suggest that DAT densities are directly associated with the pathophysiology of TD, however, that the effect of risperidone on tic symptoms in children with TD is not attributed to the change of dopaminergic system.

Dopamine Transporter Density of the Basal Ganglia in Children with Attention Deficit Hyperactivity Disorder Assessed with I-123 IPT PECT / 대한핵의학회잡지

PURPOSE: Attention deficit hyperactivity disorder (ADHD) has been known as psychiatric disorder in childhood associated with dopamine dysregulation. In present study, we investigated changes in dopamine transporter (DAT) density of the basal ganglias using I-123 N- (3-iodopropen-2-yl) -2-carbomethoxy-3beta- (4-chlorophenyl) tropane [I-123 IPT] SPECT in children with ADHD before and after methylphenidate treatment. MATERIALS AND METHOD: Nine drug-naive children with ADHD and seven normal children were included in the study. We performed brain SPECT two hours after the intravenous administration of I-123 IPT and made both quantitative and qualitative analyses using the obtained SPECT data, which were reconstructed for the assessment of specific/nonspecific DAT binding ratios in the basal ganglia. All children with ADHD reperformed [123I]IPT SPECT after treatment with methylphenidate (0.7mg/kg/d) during about 8 weeks. SPECT data reconstructed for the assessment of specific/nonspecific DAT binding ratio of the basal ganglia were compared between before and after treatment methylphenidate. We investigated correlation between the change of ADHD symptom severity assessed with ADHD rating scale-IV and specific/nonspecific DAT binding ratio of basal ganglia. RESULTS: Children with ADHD had a significantly greater specific/nonspecific DAT binding ratio of the basal ganglia comparing to normal children (Right: z = 2.057, p = 0.041; Left: z = 2.096, p = 0.032). Under treatment with methylphenidate in all children with ADHD, specific/nonspecific DAT binding ratio of both basal ganglia decreased significantly greater than before treatment with methylphenidate (Right: t = 3.239, p = 0.018; Left: t = 3.133, p = 0.020). However, no significant correlation between the change of ADHD symptom severity scores and specific/nonspecific DAT binding ratio of the basal ganglia were found. CONCLUSIONS: These findings support the complex dysregulation of the dopaminergic neurotransmitter system in children with ADHD.

Radiotracers for Functional Neuroimaging / 대한핵의학회잡지

After the development of two major techniques - SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) to image the human subjects in a three-dimensional direction in the 1980s, many radiotracers have been used for functional neuroimaging. Still it would be very important study to develop selective radiotracers for functional neuroimaging. New radiotracers will help to expand the knowledge of neurotransmitter systems and of the genetic contribution to receptor or transporter availability. Neurotransmitter depletion-restoration studies, the distribution of brain functions and their modulation by neurotransmitter system aid in better understanding and limiting the side effects of drugs used as well as newly developed. In addition, these radiotracers will be thus very useful to gain a better understanding in biochemical and pharmacological interactions in living human. This review mentions the introduction of radioligands for the functional neuroimaging. Although significant progress has been achieved in the development of new PET and SPECT ligands for in vivo imaging of those receptors and transporters, there are continuous needs of new diagnostic radioligands.

Evaluation of Striatal Dopamine Transporter Density using 123I-beta-CIT SPECT in Schizophrenic Patients Treated with Olanzapine - Pilot study / 대한핵의학회잡지

No abstract available.

Radioligands for Imaging Dopamine and Serotonin Receptors and Transporters / 대한핵의학회잡지

In the 1980s, techniques to image the human subjects in a rhree-dimensiona1 direction were developed, Two major techniques are SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) which allow the detector to detect a single photon or annihilation photons emitted from the subjects injected with radiopharmaceuticals. Since the latter two techniques can measure the density of receptors, enzymes and transporters in living human, it may be very important project to develop selective methods of labeling with radionuclides and to develop new radiopharmaceuticals. There has been a considerable interest in developing new compounds which specifically bind to dopamine and serotonin receptor and transporters, and it will be thus very useful to label those compounds with radionuclides in order to gain a better understanding in biochemical and pharmacological interactions in living human. This review rnentions the characteristics of radioligands for the imaging of dopamine and serotonin receptors and transporters. Although significant progress has been achieved in the development of new PET and SPECT ligands for in vivo imaging of those receptors and transporters, there are continuous needs of new diagnostic radioligands,

Synthesis of a Dopamine Transporter Imaging Agent, N-(3-18Ffluoropropyl)-2 -carbomethoxy-3 -(4-iodophenyl)nortropane / 대한핵의학회잡지

PURPOSE: N-(3-[18F]Fluoroporpy)-2beta- carbomethoxy-3beta-(4-iodophenyl) nortropane ([18F]FP-CIT) has been shown to be very useful for imaging the dopamine transporter. However, synthesis of this radiotracer is some what troublesome. In this study, we used a new method for the preparation of [18F]FP-CIT to increase radiochemical yield and effective specific activity. MATERIALS AND METHODS: [18F]FP-CIT was prepared by N-alkylation of nor-beta-CIT (2 mg) with 3-bromo-l-[18F]fluoropropane in the presence of Et3N (5-6 drops of DMF/CH3CN, 140 degree C, 20 min). 3-Bromo-l-[18F]fluoropropane was synthesized from 5 microliter of 3-bromo-l-trifluoromethanesulfonyloxypropane (3-bromopropyl -l-triflate) and nBu4N18F at 80 degree C. The final compound was purified by reverse phase HPLC and formulated in 13% ethanol in saline. RESULTS: 3-Bromo-l-[18F]fluoropropane was obtained from 3-bromopropyl-l-triflate and nBu4N18F in 77-80% yield. N-Alkylation of nor-beta-CIT with 3-bromo-l-[18F]fluoropropane was carried out at 140 degree C using acetonitrile containing a small volume of DMF as the solvents. The overall yield of [18F]FP-CIT was 5-10% (decay-corrected) with a radiochemical purity higher than 99% and effective specific activity higher than the one reported in the literature based on their HPLC data. The final [18F]FP-CIT solution had the optimal pH (7.0) and it was pyrogen-free. CONCLUSION:: In this study, 3-bromopropyl-l-triflate was used as the precursor for the [18F]fluorination reaction and new conditions were developed for purification of [18F]FP-CIT by HPLC. We established this new method for the preparation of [18F]FP-CIT, which gave high effective specific activity and relatively good yield.

Assessment of parkinson's disease severity with B-CIT and single-photon emission computed tomography

Previous single-photon emission computed tomography (SPECT) studies have demonstrated decreased (1231)beta-CIT (2beta-carbomethoxy-3beta(4-iodophenyl) tropane) striatal binding in Parkinson's disease (PD) patients. The present study extends our previous work by examining SPECT measures of (1231) beta-CIT binding in a larger group of PD patients with varying disease severity. Forty-six L-dopa-responsive PD patients(Hoehn-Yahr stage 1-3) had either a total of 15 SPECT scans over a 24 hr period or two scans at 12 hr and 24 hr after injection of (1231) beta-CIT. (1231) beta-CIT binding in the striatum was estimated using two indices: the specific-to nonspecific binding ratio, calculated as (striatal-cerebellar)/cerebellar radioactivity (specific binding ratio: SBR) at 24 hr postinjection as well as at its peak, which occurred at 12-24 hr postinjection; and the binding potential, the ratio of the rate constant of binding to the dopamine (DA) transporters (k3) to that of dissociation from the DA transporters (K4), as calculated by tracer kinetic modeling. The mean SBR at 24 hr postinjection, the mean peak SDR, and the mean binding potential in the striatum were all significantly correlated with Hoehn-Yahr stage, total store of UPDRS, motor score of UPDRS, and activities of daily living score of UPDRS. There were significant correlations between the sum of lateralizing UPDRS subscales (tremor, rigidity, bradykinesia) calculated for each individual limb and the SPECT measures of [123I]beta-CIT binding in the contralateral striatum. There were excellent correlations among the peak striatal SBR, the stiiatal SBR at 24 hr postinjection, and the binding potential. The results indicate that [123I]beta-CIT may be a useful marker of disease severity in PD. Additionally, the simple tissue ratio at 24 hr postinjection may be acceptable for the assessment of [123I]beta-CIT binding in PD, making repeated scanning and complicated modeling procedures less necessary. [123I]beta-CIT SPECT may be clinically useful for the early diagnosis and serial monitoring of PD.

N-( 4- 18F Fluoromethylbenzyl ) spiperone: A Selective Radiotracer for In Vivo Studies of Dopamine D2 Receptors / 대한핵의학회잡지

We evaluated the in vivo kinetics, distribution, and pharmacology of N-(4-[F] fluorornethylbenzyl)spiperone ([F]FMBS), a newly developed derivative of spiperone, as a potentially more selective #radiotrar.er for the dopamine (DA) Dz receptors. Mice received 1.9-3.7 MBq (1.8-3.6 nmol/kg) of [F]FMBS by tail vein injectivn. The time course and regional distribution of the tracer in brain were assessed. Blocking studies were carried out by intravenously preinjecting DA Dp receptor blockers (spiperone, butaclamol) as well as drugs with high affinity for DA Dr lSCH 23390), DA transporter (GBR 12909), and serotonin Sp (5-HTz) (ketanserin) sites. After injection of the tracer, the radioactivity in striatum increased steadily over time, resulting in a striatal-to-cerebellar ratio of 4.8 at 120 min postinjection. By contrast, the radioactivity in cerebellum, frontal cortex, and remaining cortex washed out rapidly. Preinjection of unlabe1ed FMBS (1 rng/kg) and spiperone (1 mg/kg) reduced [F] FMBS striatal-to-cerebellar ratio by 41Zo and 80Ya, respectively. (+)-Butaclamol(1 mg/kg) blocked 80Yo of the striatal [F]FMBS binding, while (-)-butaclamol (1 rng/kg) did not. Preinjection of SCH 23390 (1 mg/kg) and GBR 12909 (5 mg/kg) had no significant effect. On [""F]FMBS binding. Ketanserin (1 mg/kg), a ligand for the 5-H1g receptors, did not cause significant inhibition either in striatum, in frontal cortex, or the remaining cortex. The results demonstrate that [F]FMEtS labels DA Dz receptors selectively in vivo in the mouse brain. It may hold promise as a selective radiotracer for studying DA Dz receptors in vivo by PET.