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A multicenter study is under way to investigate the efficacy of allografting of embryonic mesencephalic neurons in a pig model of Parkinson's disease. We have first established that a stable parkinsonian syndrome can be established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of adult male Göttingen minipigs. We are now using positron emission tomography (PET) methods for testing the physiological responses to MPTP intoxication and the time course of the response to several treatment strategies. We now report preliminary results obtained in 11 pigs employed in the initial phase of the study; the completed study shall ultimately include 30 pigs. Animals were randomly assigned to one of five groups: 1) Control, 2) MPTP intoxication, 3) MPTP intoxication followed by allograft, 4) MPTP intoxication followed by allograft with immunosuppression, and 5) MPTP intoxication followed by allograft with immunosuppression and co-grafting of immortalized HiB5 cells, which had been manipulated to secrete glia cell line-derived neurotrophic factor (GDNF) (≈2 ng GDNF/h/10 5 cells). MPTP was administered (1 mg/kg/day, SC) for 7–10 days until the pigs had developed mild parkinsonian symptoms of muscle rigidity, hypokinesia, and impaired coordination, especially of the hind limbs. Approximately 2 weeks after the last MPTP dose, animals received a T1-weighted magnetic resonance imaging (MRI) scan, and a series of dynamic PET recordings. After the first series of PET scans, four grafts of porcine embryonic mesencephalic tissue (E28 days) were placed in each striatum of some MPTP-intoxicated pigs, using MRI-based stereotactic techniques. Immunosuppression of some animals with cyclosporin and prednisolone began just prior to surgery. Two more series of PET scans were performed at 4-month intervals after surgery. After the last scans, pigs were killed and the brains were perfused for unbiased stereological examination of cytological and histochemical markers in striatum and substantial nigra. The behavioral impairment of the animals (the “Parkinson's score”) had been evaluated throughout the 8-month period. Kinetic analysis of the first set of PET scans has indicated that the rate constant for the decarboxylation of FDOPA in catecholamine fibers was reduced by 33% in striatum of the mildly parkinsonian pigs. The rate of association of [ 11 C]NS-2214 to catecholamine uptake sites was reduced by 62% in the same groups of pigs. No significant difference was found in the binding potential of [ 11 C]raclopride to the dopamine D 2 -like receptors in striatum of the MPTP-intoxicated versus control pigs. These preliminary results are suggestive that the activity of DOPA decarboxylase may be upregulated in the partially denervated pig striatum.

Glomerular filtration rates for individual kidneys can be measured semi-quantitatively by a gamma camera using [ 99m Tc]Tc-DTPA, with limited diagnostic accuracy. A more precise measurement can be performed on a PET/CT scanner using the radiotracer [ 68 Ga]Ga-EDTA, which has been validated in animal studies. The purpose of this study was to develop an easy kit-based synthesis of [ 68 Ga]Ga-EDTA that is compliant with good manufacturing practice (GMP) and applicable for human use. The production of the cold kit and its labeling were validated, as were the radiochemical purity measurement and analytical procedures for determining the Na 2 EDTA dihydrate content in the kits. In this study, we validated a GMP kit for the simple production of [ 68 Ga]Ga-EDTA, with the intention of applicability for human use.

Background: Ketones are increasingly recognized as an important and possibly oxygen sparing source of energy in vital organs such as the heart, the brain and the kidneys. Drug treatments, dietary regimens and oral ketone drinks designed to deliver ketones for organ and tissue energy production have therefore gained popularity. However, whether ingested ketones are taken up by various extra-cerebral tissues and to what extent is still largely unexplored. It was therefore the aim of this study to use positron emission tomography (PET) to explore the whole body dosimetry, biodistribution and kinetics of the ketone tracer (R)-[1- 11 C]β-hydroxybutyrate ([ 11 C]OHB). Six healthy subjects (3 women and 3 men) underwent dynamic PET studies after both intravenous (90 min) and oral (120 min) administration of [ 11 C]OHB. Dosimetry estimates of [ 11 C]OHB was calculated using OLINDA/EXM software, biodistribution was assessed visually and [ 11 C]OHB tissue kinetics were obtained using an arterial input function and tissue time-activity curves., Results: Radiation dosimetry yielded effective doses of 3.28 [Formula: see text]Sv/MBq (intravenous administration) and 12.51 [Formula: see text]Sv/MBq (oral administration). Intravenous administration of [ 11 C]OHB resulted in avid radiotracer uptake in the heart, liver, and kidneys, whereas lesser uptake was observed in the salivary glands, pancreas, skeletal muscle and red marrow. Only minimal uptake was noted in the brain. Oral ingestion of the tracer resulted in rapid radiotracer appearance in the blood and radiotracer uptake in the heart, liver and kidneys. In general, [ 11 C]OHB tissue kinetics after intravenous administration were best described by a reversible 2-tissue compartmental model., Conclusion: The PET radiotracer [ 11 C]OHB shows promising potential in providing imaging data on ketone uptake in various physiologically relevant tissues. As a result, it may serve as a safe and non-invasive imaging tool for exploring ketone metabolism in organs and tissues of both patients and healthy individuals. Trial registration Clinical trials, NCT0523812, Registered February 10th 2022, https://clinicaltrials.gov/ct2/show/NCT05232812?cond=NCT05232812&draw=2&rank=1 ., (© 2023. The Author(s).)

The cyclotron production of gallium-68 via the 68 Zn( p,n ) 68 Ga nuclear reaction in liquid targets is gaining significant traction in clinics. This work describes (1) the synthesis of new arylamino phosphonates via the Kabachnik-Fields reaction, (2) their use for liquid-liquid extraction of 68 Ga from 1 M Zn(NO 3 ) 2 /0.01 M HNO 3 in batch and continuous flow, and (3) the use of Raman spectroscopy as a process analytical technology (PAT) tool for in-line measurement of 68 Zn. The highest extraction efficiencies were obtained with the extractants functionalized with trifluoromethyl substituents and ethylene glycol ponytails, which were able to extract up to 90% of gallium-68 in batch and 80% in flow. Only ppm amounts of zinc were co-extracted. The extraction efficiency was a function of pKa and the aqueous solubility of the extractant and showed marked concentration, solvent, and temperature dependence. Raman spectroscopy was found to be a promising PAT tool for the continuous production of gallium-68.

Background: Determination of the radiochemical purity of [ 99m Tc]NANOCIS® was performed using the procedure described in the Summary of Product Characteristics (SPC). In contrast to the clinical findings of thyroid gland accumulation indicating free [ 99m Tc] pertechnetate, the QC results showed no free [ 99m Tc]pertechnetate. This discrepancy prompted us to further investigate the described QC procedure. The aim of our study is to develop a correct QC procedure for [ 99m Tc]NANOCIS®., Method and Materials: After 99m Tc-labelling performed in accordance with the SPC, QC was performed on two stationary phases (Whatman No. 1 and ITLC-SA) with both wet and dry application spots., Results: All QC samples prepared using the method described in the SPC (Whatman No. 1 with dry application spot) indicated an acceptable labelling with a radiochemical purity over 99 %. The QC methods performed using non-SPC described methods (Whatman No. 1 with wet application spot, ITLC-SA with wet and dry application spot), show more impurities, resulting in radiochemical purity ranging between 68 % and 99 %. All results from the three QC procedures not outlined in the SPC resulted in comparable results. When comparing the QC results with imaging of the thyroid gland, if the correct TLC method is used, a clear connection was observed between low radiochemical purity, as a result of free [ 99m Tc]pertechnetate present in the prepared radiopharmaceutical, and visualisation of the thyroid gland, due to thyroid uptake of the free [ 99m Tc]pertechnetate., Conclusion: Drying the application spot on Whatman No. 1 paper indicates erroneous high labelling. To obtain a correct QC result, either an analytical method using Whatman No. 1 papers without drying of the application spot or a method using instant thin layer chromatography with a silica acid coating (ITLC-SA) should be used., Competing Interests: Declaration of competing interest No authors have any conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The effect of vascular disrupting agents in tumour therapy depends on both the immediate vascular shutdown, and on the following re-vascularization of the tumour. The aim of this study was to use a tumour model to investigate whether endothelial outgrowth cells (EOCs) influenced the short term treatment efficiency of combretastatin A-4 disodium phosphate (CA4P) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by increasing EOC tumour recruitment., Methods: In order to visualize the recruitment of EOCs to the tumours, umbilical cord blood derived human EOCs were labelled with 111Indium-tropolone in a dose of 0.37 MBq pr 3×106 cells and were injected intravenously into mice carrying a C3H mammary carcinoma on their right rear foot. DMXAA and CA4P in different concentrations and at different exposure times were used to create a hypoxic environment in the C3H mammary carcinoma in the mice. Three different mice strains with various degrees of functional immune system were used to study the homing capability of EOCs., Results: Our data showed that approximately 4% of the total injected radioactive dose per gram of tissue was found in the tumour after treatment with CA4P and DMXAA. Regardless of the concentration and the treatment duration, CA4P did not increase EOC recruitment to the tumour in comparison to EOC recruitment in control tumours in any of the 3 mice strains studied., Conclusion: Our data showed that regardless of the grade of the immune system, ranging from a fully working to a fully compromised immune system, treatment with CA4P did not increase recruitment of xenotransplanted EOCs to tumour tissue.

Introduction: Endothelial progenitor cells (EPCs) has been reported to have the potential for advancing revascularization of ischemic tissue. However, the heterogeneous nature of these cells calls for specification of the angiogenic potential of each subtype. The purpose of this study was to gain additional insight on the homing capacity of the EPC subtype, endothelial outgrowth cells (EOCs) in tumours using a well-established tumour model., Methods: (111)Indium ((111)In) - and 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) labelled EOCs derived from human umbilical cord blood were injected into mice with a C3H mammary carcinoma foot tumour. The subsequent capture of the EOCs was traced by estimation of activity in individual organs, autoradiography and fluorescence microscopy., Results: (111)In activity was found in tumour and other organs. However, varying parts of the activity originated from free (111)In lost from EOCs. Autoradiography demonstrated accumulation of (111)In activity in the tumour rim. Microscopy proved that a least part of this radioactivity originated from the presence of human derived EOCs and that those EOCs were not located in the endothelial lining of vessels, in the tumour., Conclusion: The results demonstrated the presence of xenotransplanted EOCs in the rim of a C3H mammary carcinoma. They were, however, not located in the endothelial lining of the vessels, thus indicating that their effect in vasculogenesis might be mediated via paracrine mechanisms rather than differentiating into endothelial cells (ECs) in tumour vessels., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Phosphatidylserine is translocated from the inner to the outer leaflet of the plasma membrane in the early stages of apoptosis and necrosis and in reversibly injured cells. In rabbit hearts, ischemia followed by reperfusion results in exposure of phosphatidylserine on myocytes unaffected by apoptosis or necrosis. Lactadherin was recently introduced as a highly sensitive phosphatidylserine ligand. We hypothesized that ischemic myocardial cell damage can be identified by radio-labeled lactadherin and that the ischemic area at risk (AAR) can be visualized retrospectively after reperfusion., Methods: Left anterior descending coronary artery in pigs was occluded for 20 minutes, 45 minutes or 45 minutes preceded by ischemic preconditioning. In all three groups, (99m)Tc-lactadherin was injected intravenously 30 minutes after reperfusion. The AAR was demarcated by Evans blue and the infarct size by 2,3,5,-triphenyltetrazodium chloride staining., Results: The regional myocardial uptake of (99m)Tc-lactadherin closely correlated with the AAR (r=.83, P = .001). The area of (99m)Tc-lactadherin uptake was unaltered by a shorter duration of ischemia and ischemic preconditioning (P=.23) despite significantly different infarct development (P=.001)., Conclusion: The results suggest that (99m)Tc-lactadherin can be used as a sensitive marker for AAR imaging when injected 30 minutes after reperfusion following acute ischemia., (© 2013.)

Background: The purpose of the present study was to quantify renal cell injury after ischemia and reperfusion in a pig model using (99m)Tc-lactadherin as a marker of apoptosis and (99m)Tc-sestamibi as a marker of mitochondrial dysfunction., Methods: Thirty-four pigs were randomized into unilateral renal warm ischemia of 120 (WI120) or 240 min (WI240). The glomerular filtration rate (GFR) was calculated by renal clearance of (51)Cr-ethylenediaminetetraacetic acid, and apoptosis was quantified by immunohistochemical detection of caspase-3. After 240 min of reperfusion, intravenous (99m)Tc-lactadherin or (99m)Tc-sestamibi was injected simultaneously with (153)Gd microspheres into the aorta. Ex-vivo static planar images of the kidneys were acquired for determination of the differential renal function of tracer distribution using a gamma camera., Results: In WI120, there was no significant difference in the uptake of microspheres in the ischemic and contralateral normal kidney indicating adequate perfusion (uptake in ischemic kidney relative to the sum of uptake in both kidneys; 46% ± 12% and 51% ± 5%). In WI240, the uptake of microspheres was severely reduced in both groups (17% ± 11% and 27% ± 17%). GFR was severely reduced in the post ischemic kidney in both groups. In both groups, the uptake of lactadherin was reduced (41% ± 8%, 17% ± 13%) but not different from the uptake of (153)Gd microspheres. Caspase-3-positive cell profiles were increased in the post-ischemic kidneys (p < 0.001) and increased as the length of ischemia increased (p = 0.003). In both WI120 and WI240, the amount of (99m)Tc-sestamibi in the ischemic kidney was significantly lower than the amount of (153)Gd microspheres (40 ± 5 versus 51 ± 5 and 20 ± 11 versus 27 ± 17; p < 0.05)., Conclusions: In an established pig model with unilateral renal warm ischemia, we found significantly reduced (99m)Tc-sestamibi uptake relative to perfusion in the kidneys exposed to ischemia indicating a potential ability to detect renal ischemic and reperfusion injuries. However, apoptosis was not detected using (99m)Tc-lactadherin in the post-ischemic kidneys despite increased number of caspase-3-positive cell profiles., Trial Registration: This study is approved by the Danish Inspectorate of Animal Experiments (2010/561-1837).

Background: Phosphatidylserine (PS) is a phospholipid normally located in the inner leaflet of the cell membrane. PS is translocated from the inner to the outer leaflet of the plasma membrane during the early stages of apoptosis and in necrosis. In cell and animal studies, reversible PS externalisation to the outer membrane leaflet has been observed in viable cells. Hence, PS markers have been proposed as markers of both reversibly and irreversibly damaged cells. The purpose of this experimental study in pigs was to investigate the kinetics of the newly introduced PS marker technetium-99m-labelled lactadherin (99mTc-lactadherin) in comparison with the well-known PS tracer 99mTc-annexin V with special reference to the renal handling of the tracers. The effective dose for humans was estimated from the biodistribution in 24 mice., Methods: Nine anaesthetised pigs randomly allocated into two treatment groups were administered a single injection of either 99mTc-lactadherin or 99mTc-annexin V. Renal perfusion was assessed by simultaneous injection of 51Cr-EDTA. Throughout the examinations, planar, dynamic scintigraphy of the trunk was performed, urine was collected and arterial and renal vein blood was sampled. The effective dose was estimated using the adult male phantom from the RADAR website., Results: 99mTc-lactadherin was cleared four times faster from plasma than 99mTc-annexin V, 57 ± 13 ml/min (mean ± SD) versus 14 ± 2 ml/min. 99mTc-lactadherin had a predominant uptake in the liver, whereas 99mTc-annexin V was primarily taken up by the kidneys. The estimated effective human dose after single injection of 99mTc-lactadherin and 99mTc-annexin V was 5.8 and 11 μSv/MBq, respectively., Conclusions: The high hepatic uptake of 99mTc-lactadherin compromises the use of 99mTc-lactadherin for imaging PS externalisation in the liver. Due to scatter from the liver, the use of in vivo visualisation of PS externalisation in the lower thorax and upper abdomen by 99mTc-lactadherin is challenged, but not precluded. In contrast to 99mTc-annexin, 99mTc-lactadherin has a low renal uptake and may be the preferred tracer for imaging PS externalisation in the kidneys. The effective dose after injection of 99mTc-lactadherin and 99mTc-annexin was low. Recommendations regarding the clinical use of 99mTc-lactadherin must await tracer kinetic studies in patients.

Introduction: The aim of this study was to establish a radio synthesis of (99m)Tc-HYNIC-lactadherin for in vivo studies and to perform biodistribution analysis studies in mice, comparing (99m)Tc-HYNIC-lactadherin to (99m)Tc-HYNIC-annexin V., Methods: The radiochemical purity of (99m)Tc-HYNIC-lactadherin was optimized by varying the amount of SnCl(2) in the synthesis. Furthermore, the need for bovine serum albumin (BSA) as a stabilizing agent was evaluated by following the stability by radiochemical purity measurement with and without the addition of BSA. A total of 24 mice were assigned to groups of 15 and nine mice, respectively. The animals were sacrificed at different time points; 10 min, 60 min, and 180 min., Results: The synthesis of (99m)Tc-HYNIC-lactadherin for in vivo studies has been optimized to give a stable product without addition of BSA and with a radiochemical purity of more than 95%. Approximately 60% of the injected dose of (99m)Tc-HYNIC-lactadherin was found in the liver and 4-5% could be assigned to kidneys. In contrast, (99m)Tc-HYNIC-annexin V distributes with around 13% and 45% of the injected dose in liver and kidneys, respectively. Over the experimental period (10-180 min) only small distributional changes were observed for both probes., Conclusion: In conclusion, the biodistribution of (99m)Tc-HYNIC-lactadherin, a potential new tracer for in vivo quantification of apoptosis, was evaluated. The small renal uptake of (99m)Tc-HYNIC-lactadherin makes it possible to image apoptosis in the kidneys, but the high liver clearance may be a disadvantage during myocardial perfusion.

A combinatorial synthesis of benztropine analogues is presented. Radical azidonation of 3-benzyloxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 3 to 3-(1-azidobenzyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 4 was used as a key step in the synthesis. This step was optimized by adding 10% DMF to the reaction. Reaction of 4 with phenyl magnesium bromide followed by Boc removal and N-methylation gave benztropine 1. Reaction of five-component Grignard reagents with 4 was used to create a two-dimensional library of 25 N-normethylbenztropine analogues. Further reaction of this library with five alkyl bromides was carried out to create a three-dimensional library containing 125 compounds. Screening of the libraries towards binding and inhibition of uptake of the human dopamine (hDAT), serotonin (hSERT) and norepinephrine transporters (hNET) was carried out. None of the synthesized compounds were found to be stronger than benztropine, and none were selective for inhibition of binding over monoamine uptake., (Copyright 2004 The Royal Society of Chemistry)

Integrin alpha4beta 7 is the principal gut-homing receptor, and it is assumed that expression of this specific integrin directs lymphocytes to the gut in vivo. Adoptive cellular immunotherapy against inflammatory bowel disease (IBD) may depend on the expression of integrin alpha4beta 7 to accomplish local delivery of intravenously injected regulatory T cells in inflamed gut mucosa. The present study aimed to investigate whether in vitro expanded human T cells from the colonic mucosa maintain integrin expression, show in vitro adhesion and retain in vivo gut-homing properties during cultivation. Whole colonic biopsies from healthy subjects were cultured in the presence of interleukin-2 (IL-2) and IL-4. The integrin expression of the cultured T cells was determined by flow cytometry and in vitro adhesion was assessed in a mucosal addressin cell adhesion molecule 1 (MAdCAM-1) adhesion assay. We studied the homing pattern after autologous infusion of 3 x 10(8 111)Indium ((111)In)-labelled T cells in five healthy subjects using scintigraphic imaging. The cultured CD4(+)CD45RO(+) gut-derived T cells express higher levels of integrin alpha4beta 7 than peripheral blood lymphocytes (PBLs) and show strong adhesion to MAdCAM-1 in vitro, even after (111)In-labelling. Scintigraphic imaging, however, showed no gut-homing in vivo. After prolonged transit through the lungs, the T cells migrated preferentially to the spleen, liver and bone marrow. In conclusion, it is feasible to infuse autologous T cells cultured from the gut mucosa, which may be of interest in adoptive immunotherapy. Despite high expression of the gut-homing integrin alpha4beta 7 and adhesion to MAdCAM-1 in vitro, evaluation by (111)In-scintigraphy demonstrated no gut-homing in healthy individuals.

Background and Purpose: The aim of the study was to identify hypoxia in human soft tissue sarcomas (STS) by PET scanning using the hypoxia marker [18F]-fluoromisonidazole ([18F]FMISO) and invasive oxygen sensitive probes (Eppendorf pO2 Histograph, Germany)., Materials and Methods: Thirteen patients with tumours suspected to be STS were examined by [18F]FMISO PET scanning, and eleven of these patients completed a set of Eppendorf pO2 Histograph measurements following the scanning., Results and Discussion: By histopathological diagnosis, seven tumours were shown to be STS and six tumours were benign. Ratios between tumour and muscle radioactivity and time activity curves for tumours and muscle tissue were examined in defined regions of interest. Only two malignant tumours showed [18F]FMISO uptake in higher amounts than muscle tissue over time. Hypoxia was present in both benign and malignant tumours as measured by the oxygen electrode method., Conclusions: [18F]FMISO PET in our setting seemed not to be feasible for the detection of tumour hypoxia in human soft tissue tumours. Neither did it reflect the extent of hypoxia as determined with the oxygen electrode measurements.

As part of the DaNeX study, the uptake and binding of several positron emitting tracers was recorded in brain of healthy Göttingen minipigs, in minipigs with a syndrome of parkinsonism due to MPTP intoxication, and in parkinsonian minipigs which had received intrastriatal grafts of mesencephalic neurons from fetal pigs. The specific binding of [11C]NS 2214 to catecholamine uptake sites was reduced by two thirds in striatum of the intoxicated animals, while the rate constant for the decarboxylation of [18F]fluorodopa was reduced by 50% in the intoxicated animals. Several months after grafting, both pre-synaptic markers of dopamine fibres were normal in striatum. Dopamine depletion or grafting were without effect on the cerebral perfusion rate, measured with [15O]-water, did not alter the rate of oxygen metabolism (CMRO2) in brain, and did not alter the binding potential of tracers for dopamine D1 or D2 receptors in pig striatum. However, the grafting was associated with a local increase in the binding of [11C]PK 11195, a tracer for reactive gliosis, suggesting that an immunological reaction occurs at the site of graft, which might potentially have reduced the graft patency. However, this apparent immunological response did not preclude the re-establishment of normal [18F]fluorodopa and [11C]NS 2214 uptake in the allografted striatum.

Most radioligands are substantially metabolised in peripheral organs during the course of positron emission tomography (PET) recordings. Accurate determination of plasma concentrations of unmetabolised radioligands is often important for quantification of data from PET studies. The fractions of untransformed radioligand and radioactive metabolites in plasma extracts must then be measured. Temporal changes in these fractions are influenced by the rate constant of appearance of total radioactive metabolites in plasma (apparent rate constant of metabolism in plasma, k(0)) and the net rate constant of elimination of all radioactive metabolites from plasma (k(-1)). In order to clarify the relationship between radioligand fractions and rate constants, plasma samples collected from Göttingen minipigs during PET recordings using four different binding site ligands were analysed by radio high performance liquid chromatography. The calculated plasma concentrations of parent compounds and their radioactive metabolites were used to calculate k(0) and k(-1) for 11C-labelled NNC 112, NS 2214, PK 11195 and raclopride in minipigs using a novel application of the tissue-slope intercept plot. In general, the apparent rate constant of metabolism in plasma was found to be greater in the minipig than in man. The reported kinetic analysis enables the apparent metabolism of PET radioligands in plasma to be quantified.

A multicenter study is under way to investigate the efficacy of allografting of embryonic mesencephalic neurons in a pig model of Parkinson's disease. We have first established that a stable parkinsonian syndrome can be established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of adult male Göttingen minipigs. We are now using positron emission tomography (PET) methods for testing the physiological responses to MPTP intoxication and the time course of the response to several treatment strategies. We now report preliminary results obtained in 11 pigs employed in the initial phase of the study; the completed study shall ultimately include 30 pigs. Animals were randomly assigned to one of five groups: 1) Control, 2) MPTP intoxication, 3) MPTP intoxication followed by allograft, 4) MPTP intoxication followed by allograft with immunosuppression, and 5) MPTP intoxication followed by allograft with immunosuppression and co-grafting of immortalized HiB5 cells, which had been manipulated to secrete glia cell line-derived neurotrophic factor (GDNF) (approximately 2 ng GDNF/h/10(5) cells). MPTP was administered (1 mg/kg/day, SC) for 7-10 days until the pigs had developed mild parkinsonian symptoms of muscle rigidity, hypokinesia, and impaired coordination, especially of the hind limbs. Approximately 2 weeks after the last MPTP dose, animals received a T1-weighted magnetic resonance imaging (MRI) scan, and a series of dynamic PET recordings. After the first series of PET scans, four grafts of porcine embryonic mesencephalic tissue (E28 days) were placed in each striatum of some MPTP-intoxicated pigs, using MRI-based stereotactic techniques. Immunosuppression of some animals with cyclosporin and prednisolone began just prior to surgery. Two more series of PET scans were performed at 4-month intervals after surgery. After the last scans, pigs were killed and the brains were perfused for unbiased stereological examination of cytological and histochemical markers in striatum and substantial nigra. The behavioral impairment of the animals (the "Parkinson's score") had been evaluated throughout the 8-month period. Kinetic analysis of the first set of PET scans has indicated that the rate constant for the decarboxylation of FDOPA in catecholamine fibers was reduced by 33% in striatum of the mildly parkinsonian pigs. The rate of association of [11C]NS-2214 to catecholamine uptake sites was reduced by 62% in the same groups of pigs. No significant difference was found in the binding potential of [11C]raclopride to the dopamine D2-like receptors in striatum of the MPTP-intoxicated versus control pigs. These preliminary results are suggestive that the activity of DOPA decarboxylase may be upregulated in the partially denervated pig striatum.

The study was designed to investigate the binding of [18F]Fluoromisonidazole ([18F]FMISO) and [18F]Fluoro-2-deoxy-D-glucose ([18F]FDG) in a C3H mouse mammary carcinoma. Non-anaesthetized tumour-bearing animals breathing either normal air or carbogen (to reduce tumour hypoxia) were examined by PET after tracer injection. Tumours were identified by radioactive labelling and methods of defining regions of interest (ROI) in the tumours were investigated. Reference tissue was selected elsewhere in the mice and the ratio between mean radioactivity in tumour and reference tissue was compared. The results showed a correlation between the methods of identifying ROIs and a significantly lower tumour to reference tissue ratio for carbogen-treated mice compared with controls when using [18F]FMISO. Only one of the methods showed a significant difference in the tumour labelling between treatment groups using [18F]FDG. The study supports the contention that [18F]FMISO may be able to identify hypoxia in tumours, whereas a similar role for [18F]FDG is more doubtful.