Nicotinic α4ß2 acetylcholine receptors and cognitive function in Parkinson's disease.

BACKGROUND: Idiopathic Parkinson's disease (IPD) is characterized by the clinical motor symptoms of hypokinesia, rigidity, and tremor. Apart from these motor symptoms, cognitive deficits often occur in IPD. The positive effect of cholinesterase inhibitors on cognitive deficits in IPD and findings of earlier molecular imaging studies suggest that the cholinergic system plays an important role in the origin of cognitive decline in IPD. METHODS: Twenty-five non-demented patients with IPD underwent a 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) SPECT to visualize α4ß2 nicotinic acetylcholine receptors (nAchR) and cognitive testing with the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) battery to identify domains of cognitive dysfunction. RESULTS: In the CERAD, the IPD patients exhibited deficits in non-verbal memory, attention, psychomotor velocity, visuoconstructive ability, and executive functions. After Bonferroni correction for multiple comparisons, we found significant correlations between performance of the CERAD subtests Boston Naming Test (a specific test for visual perception and for detection of word-finding difficulties) and Word List Intrusions (a specific test for learning capacity and memory for language information) vs binding of α4ß2 nAchR in cortical (the right superior parietal lobule) and subcortical areas (the left thalamus, the left posterior subcortical region, and the right posterior subcortical region). CONCLUSIONS: These significant correlations between the results of the CERAD subtests and the cerebral α4ß2 nAchR density, as assessed by 5-I-A-85380 SPECT, indicate that cerebral cholinergic pathways are relevant to cognitive processing in IPD.

Patients with recurrent glioblastoma multiforme. Initial experience with p-[(131)I]iodo-L-phenylalanine and external beam radiation therapy.

AIM: The objective of this study was to assess the feasibility, dosimetry, tolerability and efficacy of systemically administrated p-[(131)I]iodo-L-phenylalanine ((131)IPA) combined with hypo-fractionated external beam radiation therapy (EBRT) in patients with recurrent glioblastoma multiforme (GBM). PATIENTS, METHODS: Five patients (2 women, 3 men, aged 27-69) with recurrent GBM and exhaustion of regular therapy options were included. All had a positive O-(2-[(18)F]Fluoroethyl)-L-tyrosine positron emission tomography (FET-PET) and pretherapeutic dosimetry was performed. Tumour targeting was verified by (131)IPA-SPECT up to six days after radiotracer administration. After (131)IPA therapy, patients were treated with hypo-fractionated EBRT in six fractions of 5 Gy (n = 4) or in eleven fractions of 2 Gy in one case. RESULTS: Based on the individual dosimetry, the patients received a single intravenous administration of 2 to 7 GBq of (131)IPA, resulting in radiation absorbed doses to the blood of 0.80-1.47 Gy. The treatment was well tolerated; only minor complaints of nausea and vomiting that responded to ondansetron and pantoprazol were noticed in the first two patients. After preventive medication, the last three patients had no complaints during therapy. In none of the patients a decrease of leukocyte or thrombocyte counts below the baseline level or the lower normal limit was observed. Tumour doses from (131)IPA were low (≤ 1 Gy) and all patients died three to eight (median 5.5) months after therapy. CONCLUSION: In this initial experience, treatment of GBM with (131)IPA in combination with EBRT was demonstrated to be safe and well tolerated, but less effective than suggested by the animal studies.

Para-[(123)I]iodo-L-phenylalanine in patients with pancreatic adenocarcinoma: tumour uptake, whole-body kinetics, dosimetry.

UNLABELLED: Recently, p-[(123)I]iodo-L-phenylalanine (IPA) was clinically validated for brain tumour imaging. Preclinical studies demonstrated uptake of IPA into pancreatic adenocarcinoma suggesting its diagnostic application in patients with pancreatic tumours. The aim was to study the tumour uptake of IPA in patients with pancreatic adenocarcinoma and to analyse its biodistribution and dosimetry to assess the radiation dose resulting from its diagnostic use. PATIENTS, METHODS: Seven patients with pancreatic adenocarcinoma underwent whole-body scintigraphies and SPECT up to 24 h after administration of 250 MBq of IPA. Tumour uptake of IPA was assessed visually. Time activity curves and the corresponding residence times were determined for whole-body, kidneys, liver, spleen, lung, heart content, brain, and testes. Mean absorbed doses for various organs and the effective dose were assessed based on the MIRD formalism using OLINDA/EXM. RESULTS: IPA exhibited no accumulation in proven manifestations of pancreatic adenocarcinomas. IPA was exclusively eliminated by the urine and showed a delayed clearance from blood. Residence times were 0.26 +/- 0.09 h for kidneys, 0.38 +/- 0.19 h for liver, 0.15 +/- 0.07 h for spleen, 0.51 +/- 0.20 h for lungs, 0.22 +/- 0.07 h for heart content, 0.11 +/- 0.05 h for brain, 0.014 +/- 0.005 h for testes and 6.4 +/- 2.2 h for the remainder. The highest absorbed doses were determined in the urinary bladder wall and in the kidneys. According to the ICRP 60 the effective dose resulting from 250 MBq IPA was 3.6 +/- 0.7 mSv. CONCLUSION: Para-[(123)I]iodo-L-phenylalanine can be used in diagnostic nuclear medicine with acceptable radiation doses. Besides its proven validity for brain tumour imaging, IPA does not appear to be suitable as tracer for pancreatic cancer.

Striatal FP-CIT uptake differs in the subtypes of early Parkinson's disease.

In idiopathic Parkinson's disease (PD), a tremor-dominant type (TDT), an akinetic-rigid type (ART), and a mixed type (MT) are distinguished. We compared cerebral [I-123]FP-CIT SPECT in the PD subtypes (67 patients Hoehn and Yahr stage 1:26 with ART, 19 with MT, 22 with TDT). We measured the ratios putamen/occipital lobe binding and caudate nucleus/occipital lobe binding. Parkinsonian motor symptoms were quantified by UPDRS motor scale. In both putamen and caudate nucleus contralateral to the clinically affected body side TDT patients showed a significantly higher FP-CIT uptake than ART or MT patients (ANOVA; p<0.01). Contralateral putamen and caudate nucleus FP-CIT uptake correlated significantly with severity of rigidity (p<0.01) and hypokinesia (p<0.01) but not with severity of resting or postural tremor (p>0.05). The missing correlation between striatal FP-CIT uptake and tremor suggests, that further systems besides the nigrostriatal dopaminergic system may contribute to generation of parkinsonian tremor.

Initial evaluation of the feasibility of single photon emission tomography with p-[123 I]iodo-L-phenylalanine for routine brain tumour imaging.

p-[123I]iodo-L-phenylalanine (IPA) is a recently described radiopharmaceutical which is highly accumulated in gliomas. The present investigation was designed to evaluate the feasibility of single photon emission tomography (SPET) with IPA to image brain tumours under routine clinical conditions. Using a dual- and a triple-headed SPET camera, whole-body kinetic and brain SPET, as well as plasma, urinary and dosimetric analysis were determined in four patients with gliomas after intravenous injection of IPA. Results obtained by IPA SPET were retrospectively compared with histopathology, magnetic resonance imaging and positron emission tomography with [18F]fluorodeoxyglucose. Tumour lesions were clearly demonstrated by IPA SPET at 30 min, 1h and 4.5h post-injection, even in patients with low grade gliomas. In patients with glioblastoma, excellent visualization of the tumour was possible even at 7h p.i., indicative of the high retention of the radiopharmaceutical in cerebral gliomas. Analysis of the radioactivity in plasma and urine attested to the high in vivo stability of IPA. Blood clearance was rapid (> 65% after 10 min) and IPA was excreted predominantly by the kidneys, the urinary radioactivity excretion ranging from 27% at 1h to 54% of injected doses at 5h p.i. The average effective dose for adults was estimated to be 0.0152mSv*MBq(-1), leading to an effective dose of 3.8mSv in a typical brain SPET investigation with 250 MBq IPA. This result strongly suggests that IPA is a potentially valuable brain tumour imaging agent for widespread clinical studies with SPET. Its high specific tumour uptake and retention even in low grade gliomas represent a major advantage compared to presently available SPET radiopharmaceuticals. Moreover, the radiation dose estimates indicate that clinical use of IPA will result in acceptable radiation dose levels in humans.

PET studies of 18F-memantine in healthy volunteers.

Previous studies in mice and PET investigations in a Rhesus monkey showed that the regional uptake of 18F-memantine could be blocked by pharmacological doses of memantine and (+)-MK-801. In the present study, the binding characteristics of 18F-memantine was examined in five healthy volunteers. In humans, 18F-memantine was homogeneously distributed in gray matter i.e. cortex and basal ganglia regions, as well as the cerebellum. No radioactive metabolites were detected in plasma during the time-frame of the PET studies. The uptake of 18F-memantine in receptor-rich regions such as striatum and frontal cortex could be well described by a 1-tissue compartment model. The DV" values of all gray matter regions were similar and ranged from 15 to 20 ml/ml. The white matter showed lower DV" values of 15 +/- 1.4 ml/ml. These results suggest that 18F-memantine distribution in human brain does not reflect the regional NMDA receptor concentration, and therefore, this radioligand is not suitable for the PET imaging of the NMDA receptors.

Preparation and investigation of tumor affinity, uptake kinetic and transport mechanism of iodine-123-labelled amino acid derivatives in human pancreatic carcinoma and glioblastoma cells.

In developing radioiodinated agents for pancreatic and brain tumor imaging by single photon emission tomography (SPET), we prepared p-amino-3-[123I]iodo-l-phenylalanine (IAPA), p-[123I]iodo-l-phenylalanine (IPA), L-8-[123I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (ITIC) and L-3-[123I]iodo-alpha-methyl-tyrosine (IMT) in radiochemical yields up to 95%, and we investigated their uptake in human pancreatic carcinoma and glioblastoma cells as well as the mechanisms promoting the tumor uptake. The radiopharmaceutical uptake into tumor cells was rapid (t(1/2) < or = 5 min) and temperature- and pH-dependent. The radioactivity concentration in tumor cells varied from 10 to 33% of the total activity (105-310 cpm/1000 cells) following a 30-min incubation at 37 degrees C (pH 7.4). In comparison, accumulation of the radiopharmaceuticals into normal brain and pancreatic tissue remained relatively low. Depolarizing the plasma membrane potential in high K+ buffer significantly altered the radioactivity concentration in the tumor cells, suggesting that membrane potential plays a certain role in the cellular uptake. Competitive inhibition experiments with specific amino acid transport inhibitors indicated that the uptake of IAPA, IPA and IMT into human pancreatic carcinoma and glioblastoma cells is predominantly mediated by the L and ASC transport systems, while no substantial involvement of the transport system A in their tumor uptake could be demonstrated. In contrast, results of the present investigation indicated that ITIC is not taken up into tumor cells via the common neutral amino acid carrier systems, including the A, L and ASC system. Furthermore, preloading with naturally occurring L-amino acids failed to stimulate the cellular uptake of the radiopharmaceuticals. These data indicate that the investigated radiopharmaceuticals exhibit interesting characteristics with promise for in vivo tumor investigations to ascertain their potential as radioligands for glioma and pancreatic carcinoma imaging by SPET.

Investigation of iodine-123-labelled amino acid derivatives for imaging cerebral gliomas: uptake in human glioma cells and evaluation in stereotactically implanted C6 glioma rats.

In developing iodine-123-labelled amino acid derivatives for imaging cerebral gliomas by single-photon emission tomography (SPET), we compared p-[123I]iodo-L-phenylalanine (IPA), L-[123I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (ITIC) and L-3-[123I]iodo-alpha-methyltyrosine (IMT) with regard to their uptake in human glioblastoma T99 and T3868 cells, and thereafter studied the mechanisms promoting the cellular uptake. The potential of the 123I-iodinated agents for use as SPET radiopharmaceuticals was evaluated in healthy experimental rats as well as in rats with stereotactically implanted C6 gliomas. The radiopharmaceutical uptake into glioblastoma cells was rapid, temperature and pH dependent, and linear during the first 5 min. Equilibrium was reached after 15-20 min, except in the case of ITIC, the initial uptake of which gradually decreased from 15 min onwards. The radioactivity concentration in glioma cells following 30-min incubation at 37 degrees C (pH 7.4) varied from 11% to 35% of the total activity per million cells (ITIC < IMT < or = IPA). Competitive inhibition experiments using alpha-(methylamino)-isobutyric acid and 2-amino-2-norbornane-carboxylic acid, known as specific substrates for systems A and L, respectively, as well as representative amino acids preferentially transported by system ASC, indicated that IPA, like IMT, is predominantly mediated by the L and ASC transport systems, while no significant involvement of the A transport system could be demonstrated. By contrast, none of the three principal neutral amino acid transport systems (A, L and ASC) appear to be substantially involved in the uptake of ITIC into glioblastoma cells. Analysis of uptake under conditions that change the cell membrane potential, i.e. in high K+ medium, showed that the membrane potential plays an important role in ITIC uptake. Alteration of the mitochondrial activity by means of valinomycin or nigericin induces a slight increase or decrease in the radiopharmaceutical uptake, suggesting a minor contribution of the mitochondria in the uptake. IPA, IMT and ITIC passed the blood-brain barrier, and thereafter showed efflux from the brain. The radioactivity concentration in healthy rat brain 15 min following intravenous injection varied from 0.07% (ITIC) to 0.27% ID/g (IPA). In comparison, the brain uptake in the stereotactically implanted C6 glioma rats was substantially higher (up to 1.10% ID/g 15 min p.i.), with tumour-to-background ratios greater than 4. These data indicate that IPA and ITIC, like IMT, exhibit interesting biological characteristics which hold promise for in vivo brain tumour investigations by SPET.

[A simple and rapid routine preparation of no-carrier added meta-I-123- and I-131-iodobenzylguanidine (I-123-MIBG and I-131-MIBG) for clinical nuclear medicine applications]. / Einfache und schnelle Routineherstellung von ungeträgertem Meta-I-123- und I-131-Iodbenzylguanidin (I-123-MIBG und I-131-MIBG) für die klinischen nuklearmedizinischen Anwendungen.

AIM: Low specific activity meta-iodobenzylguanidine (I-123/I-131-MIBG) is currently used in the assessment of abnormalities in the myocardial neuroadrenergic function as well as in the management of neuroendocrine tumors. In recent studies an enhanced cardiac and tumor uptake were reported by the use of high specific activity radiopharmazeuticals, suggesting a potential clinical benefit of no-carrier-added (n.c.a.) I-123/I-131-MIBG. In this paper we describe a simple and improved preparation of I-123-MIBG and I-131-MIBG for routine clinical application, feasible in any nuclear medicine department. METHODS: N.c.a I-123-MIBG and n.c.a. I-131-MIBG were prepared by Cu(I)-assisted [I-123/I-131]iodo-debromination at 170-175 degrees C with 86 +/- 6% and 80 +/- 10% radiochemical yield respectively and high specific activity (> or = 4.3 TBq/mumol and > or = 0.21 TBq/mumol), starting from meta-bromobenzylguanidine (MBBG). The total time of synthesis including the HPLC purification and the preparation of the injectable solution was less than 60 min. RESULTS: Neither rechromatography by HPLC nor TLC gave any indication of disintegration products in the injection solution up to 8 h after preparation. Moreover, biological testings confirmed that the buffered and sterile-filtered n.c.a. I-123-MIBG and n.c.a. I-131-MIBG solutions are isotonic, sterile and apyrogenic and thus suitable as injectable solutions for clinical use. CONCLUSION: High specific activity I-123-MIBG and I-131-MIBG could now be prepared by a simple one-step reaction giving rise to high radiochemical yields and high purity for a widespread clinical applications. Therefore, this encourages clinical validations on a large scale to answer the question of whether n.c.a. I-123-MIBG and I-131-MIBG could play an important role in the assessment of the myocardial sympathetic nervous dysfunction as well as in the diagnosis and therapy of neuroendocrine tumors.

Improved labelling of no-carrier-added 123I-MIBG and preliminary clinical evaluation in patients with ventricular arrhythmias.

Meta-[123I]iodobenzylguanidine (123I-MIBG) is currently used to assess myocardial sympathetic innervation by single photon emission tomography (SPET). In recent studies, an enhanced cardiac uptake of 123I-MIBG with high specific activity has been reported, suggesting the clinical potential of no-carrier-added (n.c.a.) 123I-MIBG in the assessment of abnormalities in cardiac sympathetic function. This paper describes the preparation of n.c.a. 123I-MIBG by non-isotopic Cu(I)-assisted [123I]iododebromination and by [123I]iododestannylation, both resulting in n.c.a. 123I-MIBG with radiochemical yields of 88 +/- 6% and high specific activity (> or = 6.3 TBq.mumol-1) in a total synthesis time of less than 50 min. The diagnostic potential of n.c.a. 123I-MIBG (> 6.3 TBq.mumol-1) was studied in 13 patients (nine patients with malignant ventricular arrhythmias and four patients suspected of phaeochromocytoma) and compared to commercial 123I-MIBG (approximately 75 MBq.mumol-1) using a dual-headed SPET camera (MULTISPECT II). High specific activity results in higher 123I-MIBG uptake in the heart and in the liver in all patients. The calculated heart-to-lung and heart-to-liver count ratios 4.5 h post-injection increased by 22 +/- 6% and 10 +/- 5% with n.c.a. 123I-MIBG compared to commercial 123I-MIBG respectively. In contrast, no significant correlation between the specific activity of 123I-MIBG and lung uptake could be established in this study. Analysis of radioactivity in blood after the intravenous injection of n.c.a. and commercially available 123I-MIBG showed an initial rapid clearance of radioactivity from blood, followed by a plateau from 60 min onwards. Within the first 24 h, more than 85% of the plasma activity was unchanged 123I-MIBG. The free 123I-iodide concentration determined 24 h post-injection was 2 +/- 1% with commercial 123I-MIBG and 3 +/- 2% with n.c.a. 123I-MIBG. In conclusion, the results of this investigation indicate that n.c.a. 123I-MIBG is a promising clinical tool for imaging myocardial sympathetic dysfunction by SPET. High specific activity n.c.a. 123I-MIBG can now be prepared by simple one-step methods giving high radiochemical yields and high purity suitable for clinical application. This encourages the further clinical validation of n.c.a. 123I-MIBG on a large scale.

Fluorine-18 radiolabelling, biodistribution studies and preliminary PET evaluation of a new memantine derivative for imaging the NMDA receptor.

A synthetic method has been established for preparing [18F]1-amino-3-fluoromethyl-5-methyl-adamantane ([18F]AFA). Biodistribution of the radiotracer in mice showed high brain uptake. The peak uptake (3.7% I.D/g organ) for the brain occurred at 30 min after injection. Accumulation of radioactivity in mouse brain was consistent with the known distribution of the NMDA receptors. The binding of [18F]AFA to the phencyclidine (PCP) binding sites of the NMDA receptor complex and the sigma recognition sites in a Rhesus monkey was also examined using positron emission tomography (PET). The regional brain distribution of [18F]AFA was changed by memantine and by (+)-MK-801, indicating competition for the same binding sites. Treatment with haloperidol caused a marked reduction of radioactivity uptake in all the brain regions examined. (-)-Butaclamol, which has pharmacological specificity for sigma sites, did not have any significant effects.

Evaluation of l-3-[123I]iodo-alpha-methyltyrosine SPET and [18F]fluorodeoxyglucose PET in the detection and grading of recurrences in patients pretreated for gliomas at follow-up: a comparative study with stereotactic biopsy.

Based on the results of stereotactic biopsy, we evaluated in a prospective fashion the efficiency of l-3-[123I]iodo-alpha-methyltyrosine-single-photon emission tomography (SPET) and [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in the detection and grading of recurrences in patients previously treated for gliomas. The patient population comprised 30 individuals, nine with astrocytomas of grade II, ten with astrocytomas of grade IV, three with oligoastrocytomas of grade II, six with oligodendrogliomas of grade II and two with anaplastic oligodendrogliomas of grade III) suspected of recurrence and scheduled for further treatment. IMT SPET data were acquired using either by dual-or a triple-headed SPET camera, Multispect 2/3. FDG uptake was measured with an ECAT ART PET camera. Two independent observers classified PET and SPET images as positive or negative for tumour tissue. Uptake of FDG and IMT was evaluated visually and, in the case of IMT, also quantitatively by calculating the ratios between tracer accumulation in the lesion and the unaffected contralateral regions of reference using the region of interest (ROI) technique. The PET and SPET results were compared with the histopathological findings obtained either by stereotactic biopsy or in one case by open surgery. Glucose metabolism and amino acid uptake of recurrences of brain tumours as assessed by FDG-PET and IMT-SPET correlated highly with the histopathological findings. Based on the histopathological data, FDG-PET and IMT-SPET findings confirmed recurrence in all cases of high-grade gliomas (IV). A difference could be demonstrated in low-grade (II-III) tumour recurrences. True-positive IMT-SPET results were found in 86% of grade III and 75% of grade II recurrences, whereas FDG-PET yielded a sensitivity of 71% in tumours of grade III and 50% in those of grade II. With respect to the grade of malignancy of brain tumours at recurrence, IMT-SPET, in contrast to FDG-PET, does not permit adequate in vivo grading of non-mixed brain tumours of astrocytic or oligodendroglial origin. However, in this study FDG-PET did not permit discrimination between upgrading of low-grade oligoastrocytomas (II) into anaplastic oligodendrogliomas (III) and upgrading into glioblastomas (IV) The results of this study indicate that FDG-PET and IMT-SPET are equivalent to stereotactic biopsy in their ability to identify high-grade tumours at recurrence. IMT-SPET proved to be superior to FDG-PET in confirming low-grade recurrences. In the case of suspected progression of the grade of malignancy in ordinary gliomas, FDG-PET correlated significantly with the histopathological grading, whereas IMT-SPET did not. However, tumour grading by FDG-PET has a limitation in mixed brain tumours in that it is not possible to discriminate between progression of the oligo- versus the astrocytic tumour entity. In this case histopathological evaluation of the tumour grade remains necessary.

123I-MSP and F[11C]MSP: new selective 5-HT2A receptor radiopharmaceuticals for in vivo studies of neuronal 5-HT2 serotonin receptors. Synthesis, in vitro binding study with unlabelled analogues and preliminary in vivo evaluation in mice.

In vitro binding study on bovine brain membranes using [3H]SCH23390, [3H]spiperone, [3H]prazosin and [3H]RP62203 as radioligands (for D1, D2, alpha1 and 5-HT2A receptors respectively) indicate that the new butyrophenones 8-[3-(4-fluorobenzoyl)propyl]-1-methyl-1,3,8-triazaspiro[4,5]de can-4-one (FMSP) and 8-[3-(4-iodobenzoyl)propyl]-1-methyl-1,3,8-triazaspiro[4,5]deca n-4-one (IMSP) exhibit a significantly higher selectivity for the 5-HT2A over D1, D2 and alpha1 receptors. Consequently, the radiolabelled analogues F[11C]MSP and 123I-MSP were prepared in attempt to obtain potential radiopharmaceuticals for in vivo imaging of neuronal 5-HT2A receptors with positron emission tomography (PET) and single photon emission tomography (SPET). F[11C]MSP was synthesized by reaction of [11C]CH3I with 8-[3-(4-fluorobenzoyl)propyl]-1,3,8-triazaspiro[4,5]decan-4- one (DMSP) in 12 +/- 3% radiochemical yield, whereas 123I-MSP was obtained in 82 +/- 8% radiochemical yield by a no-carrier-added Cu(I)-assisted [123I]iododebromination of 8-[3-(4-bromo-benzoyl)propyl]-1-methyl-1,3,8-triazaspiro[4,5]de can-4-ene (BrMSP). In vivo pharmacokinetic and brain binding characterization of 123I-MSP assessed in mice following intravenous injection, showed a fast clearance of 123I-MSP from blood and relatively high initial uptakes in the liver, kidneys and in the lung. Significant uptake and long retention were observed in the brain (up to 1.64% i.d., 60 min p.i.), with a regional accumulation of radioactivity consistent with the reported 5-HT2A receptors distribution in the brain. Frontal cortex to cerebellum ratio of 3.5 was calculated at 60 min p.i. Furthermore, the initial brain uptake was significantly reduced after pretreatment of the animals with ritanserin, a selective 5-HT2 antagonist, and by preinjection of the non-radiolabelled analog IMSP, thus indicating the specificity of the brain uptake. These data suggest that 123I-MSP may be a promising compound for studying the serotoninergic 5-HT2 receptors with SPET. Due to the low specific activity of F[11C]MSP currently obtained by the [11C]methylation reaction, systematic in vivo investigation of F[11C]MSP are as yet not feasable.

[Contribution of nuclear medicine to the diagnosis of recurrent brain tumors and cerebral radionecrosis]. / Beitrag der Nuklearmedizin zur Diagnostik des Hirntumorrezidivs und der zerebralen Radionekrose.

The evaluation of brain tumor recurrence and therapy-induced benign changes following surgery and/or irradiation is a diagnostic challenge for imaging methods based on either morphology (cCT/MRI) or function (SPECT/PET). Current literature and the present data of our own patients demonstrate the diagnostic efficiency of IMT-SPECT and FDG-PET in the detection of recurrence and in-vivo grading. Thirty-nine patients suspected of brain tumor recurrence at follow-up were studied by FDG-PET and IMT-SPECT. Thirty-four of 39 patients showed recurrences; in 12 cases even a change in the grade of malignancy was observed. All high-grade recurrences could be confirmed by either methods. IMT-SPECT showed a higher sensitivity in detecting low-grade tumors at recurrence. In contrast to IMT-SPECT, FDG-PET supports sufficient in-vivo grading. Both methods can be used to differentiate between tumor recurrence and radionecrosis. In conclusion the results of our study demonstrate the efficiency of IMT-SPECT and FDG-PET in confirming recurrences and determining the actual tumor grade.

[Comparison of 51Cr-EDTA with 99m-Tc-DTPA slope clearance for estimation of glomerular filtration rate using the one compartment model]. / Vergleich der 51Cr-EDTA-mit der 99mTc-DTPA-Slope-Clearance zur Bestimmung der glomerulären Filtrationsrate nach dem Ein-Kompartiment-Modell.

AIM: Of this study is to determine the relationship between 51Cr-EDTA and 99mTc-DTPA slope clearance applying the "one-compartment model". METHODS: The "one-compartment model" was chosen to calculate and to compare the glomerular filtration rates of 25 patients with normal and pathological creatinin values after injection of 51Cr-EDTA and 99mTc-DTPA simultaneously. RESULTS: The two clearance values correlated well (r = 0.996), and the 99mTc-DTPA clearance was systematically higher (28%). The 99mTc-DTPA was calculated and compared after taking three plasma samples. Taking two samples, only minor differences were seen and the correlation was high (r = 0.992). CONCLUSION: The results of this study encouraged us to adopt the use of 99mTc-DTPA instead of 51Cr-EDTA in determining the glomerular filtration applying the "one-compartment model" in slope with two plasma samples.

Electrophysiological study, biodistribution in mice, and preliminary PET evaluation in a rhesus monkey of 1-amino-3-[18F]fluoromethyl-5-methyl-adamantane (18F-MEM): a potential radioligand for mapping the NMDA-receptor complex.

The effect of the fluorinated memantine derivative and NMDA receptor antagonist, 1-amino-3-fluoromethyl-5-methyl-adamantane (19F-MEM), at the NMDA receptor ion channel was studied by patch clamp recording. The results showed that 19F-MEM is a moderate NMDA receptor channel blocker. A procedure for the routine preparation of the 18F-labelled analog 18F-MEM has been developed using a two-step reaction sequence. This involves the no-carrier-added nucleophilic radiofluorination of 1-[N-(tert-butyloxy)carbamoyl]-3-(toluenesulfonyloxy)methyl- 5-methyl-adamantane and the subsequent cleavage of the BOC-protecting group using aqueous HCI. The 18F-MEM was obtained in 22 +/- 7% radiochemical yield (decay-corrected to EOB) in a total synthesis time including HPLC purification of 90 min. A biodistribution study after i.v. injection of 18F-MEM in mice showed a fast clearance of radioactivity from blood and relatively high initial uptake in the kidney and in the lung, which gradually decreased with time. The brain uptake was high (up to 3.6% ID/g, 60 min postinjection) with increasing brain-blood ratios: 2.40, 5.10, 6.33, and 9.27 at 5, 30, 60, and 120 min, respectively. The regional accumulation of the radioactivity in the mouse brain was consistent with the known distribution of the PCP recognition site. Preliminary PET evaluation of the radiotracer in a rhesus monkey demonstrated good uptake and prolonged retention in the brain, with a plateau from 35 min onwards p.i. in the NMDA receptor-rich regions (frontal cortex, striata, and temporal cortex). Delineation of the hippocampus, a region known to contain a high density of NMDA receptors, was not possible owing to the resolution of the PET tomograph. The regional brain uptake of 18F-MEM was changed by memantine and by a pharmacological dose of (+)-MK-801, indicating competition for the same binding sites. In a preliminary experiment, haloperidol, a dopamine D2 and sigma receptor antagonist, decreased the binding of 18F-MEM from the brain regions examined, suggesting that binding was also occurring to the sigma recognition sites.

Preparation of 8-[3-(4-fluorobenzoyl)-propyl]-1-(4-[123I] iodobenzoyl)-1,3,8-triazaspiro[4,5]decan-4-one: a novel selective serotonin 5-HT2 receptor agent.

In our attempt to develop radioiodinated serotonin 5-HT2 receptor imaging agents for routine clinical application with single photon emission computed tomography (SPECT), the [123I]iodinated compound 8-[3-(4-fluorobenzoyl)-propyl]1-(4-[123I]iodobenzoyl)- 1,3,8-triazaspiro[4,5]decan-4-one [123I]IBSP was prepared via no-carrier-added Cu(I)-assisted radio-iododebromination in acetic acid, followed by purification by means of reversed-phase HPLC in 70-90% radiochemical yield and high specific activities at a total synthesis time of 50 min. Moreover, [123I]-IBSP is stable up to 48 h in aqueous solution at room temperature and revealed appropriate lipophilicity (logP = 2.8) for good diffusion through the blood-brain-barrier. Competitive binding studies on rat brain membranes using [3H]ketanserin, [3H]SCH23390, and [3H]spiperone as radioligands (for 5-HT2, D1 and D2 receptors, respectively) indicated that IBSP has high affinity and selectivity for the serotonin 5-HT2 receptor (Ki = 7.0 nM) over the dopamine D2 (Ki = 153 nM) and D1 receptors (Ki = 265 nM). These data suggest that [123I]-IBSP may be a promising compound for studying 5-HT2 receptors with SPECT.

Non-invasive grading of primary brain tumours: results of a comparative study between SPET with 123I-alpha-methyl tyrosine and PET with 18F-deoxyglucose.

Use of iodine-123-alpha-methyl tyrosine (123I-IMT) allows investigation of the amino acid transport rate in gliomas. It was the aim of this study to compare the value of measurement of glucose metabolism with that of measurement of 123I-IMT uptake for the non-invasive grading of brain tumours. The study population comprised 23 patients with histopathologically proven primary brain tumours; 14 had high-grade gliomas, and nine low-grade brain neoplasms. Glucose metabolism was studied using an ECAT EXACT 47 positron emission tomography (PET) camera and fluorine-18 fluorodeoxyglucose (18F-FDG); 123I-IMT uptake was measured with the triple-headed single-photon emission tomography (SPET) camera, MULTISPECT 3. 18F-FDG and 123I-IMT uptake was quantified as ratios between the uptake by the tumour and contralateral regions of reference. Glucose metabolism and amino acid uptake of the brain tumours correlated significantly (r=0.71, P <0.001). Assuming discrimination thresholds between high-grade and low-grade tumours of 0.8 for 18F-FDG uptake and 1.8 for 123I-IMT uptake, the accuracy values of 18F-FDG PET and 123I-IMT SPET for differentiating between high-grade and low-grade tumours were 21/23 (91%) and 19/23 (83%), respectively. The difference in diagnostic performance was not significant on receiver operating characteristic analysis (P >0.4). It is concluded that there is no major difference between the PET investigation of glucose metabolism and the less expensive SPET measurement of amino acid uptake in terms of their accuracy in evaluating the malignancy grade of primary brain tumours. This encourages the performance of further studies to analyse the potential impact of 123I-IMT SPET on the therapeutic management of patients with brain tumours.

Uptake of iodine-123-alpha-methyl tyrosine by gliomas and non-neoplastic brain lesions.

Using single-photon emission tomography (SPET), the radiopharmaceutical l-3-iodine-123-alpha-methyl tyrosine (IMT) has been applied to the imaging of amino acid transport into brain tumours. It was the aim of this study to investigate whether IMT SPET is capable of differentiating between high-grade gliomas, low-grade gliomas and non-neoplastic brain lesions. To this end, IMT uptake was determined in 53 patients using the triple-headed SPET camera MULTISPECT 3. Twenty-eight of these subjects suffered from high-grade gliomas (WHO grade III or IV), 12 from low-grade gliomas (WHO grade II), and 13 from non-neoplastic brain lesions, including lesions after effective therapy of a glioma (five cases), infarctions (four cases), inflammatory lesions (three cases) and traumatic haematoma (one case). IMT uptake was significantly higher in high-grade gliomas than in low-grade gliomas and non-neoplastic lesions. IMT uptake by low-grade gliomas was not significantly different from that by non-neoplastic lesions. Diagnostic sensitivity and specificity were 71% and 83% for differentiating high-grade from low-grade gliomas, 82% and 100% for distinguishing high-grade gliomas from non-neoplastic lesions, and 50% and 100% for discriminating low-grade gliomas from non-neoplastic lesions. Analogously to positron emission tomography with radioactively labelled amino acids and fluorine-18 deoxyglucose, IMT SPET may aid in differentiating high-grade gliomas from histologically benign brain tumours and non-neoplastic brain lesions; it is of only limited value in differentiating between non-neoplastic lesions and histologically benign brain tumours.