A remote system for the synthesis of copper-62 labeled Cu(PTSM).
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Copper Radioisotopes↗
Biomedical subjects
C J Mathias
Publications and source records attributed to C J Mathias.
Investigation of copper-PTSM as a PET tracer for tumor blood flow.
Copper-PTSM has been shown in previous studies to act as a fluid microsphere and to be useful in quantitating blood flow in brain, myocardium, and kidneys. In this study we have evaluated this agent as a PET tumor blood flow agent. 64Cu- or 67Cu-labeled Cu-PTSM was administered (i.v.) to Golden Syrian hamsters with colorectal carcinoma cell implants (GW39). One minute prior to sacrifice (10-60 min after Cu-PTSM was administered) 125I-iodoantipyrine (125I-IAP), an agent known to measure tumor blood flow, was administered intravenously by a 3-stage, 1 min ramp infusion. Following sacrifice, samples of tumor and brain were removed (within 40s) and the tumor and brain levels of Cu-PTSM and iodoantipyrine determined. Since the brain uptake of both Cu-PTSM and IAP is perfusion rate limited, the brain was used as a reference organ to normalize tumor levels of the two tracers. The plot of Cu-PTSM versus 125I-IAP tumor/brain ratios showed a good linear correlation (r value of 0.97), suggesting that Cu-PTSM could be used to quantify tumor blood flow. Since the mechanism of Cu-PTSM trapping is likely to be due to glutathione levels in the tissue, and because tumor tissue glutathione levels might vary, the temporal uptake of Cu-PTSM was investigated by PET imaging both the tumor-bearing hamsters and approximately 300 g Copenhagen rats bearing R3227 prostate tumors. The tumors were clearly visualized and the retained copper radioactivity in the tumor was constant over the 30 min imaging period.
Animals↗
Positron labeled muscarinic acetylcholine receptor antagonist: 2- and 4-[18F]fluorodexetimide. Syntheses and biodistribution.
Two 18F-labeled analogues of dexetimides, 2-[18F]fluorodexetimide (2-FDEX) and 4-[18F]fluorodexetimide (4-FDEX), were prepared and evaluated in vivo as possible agents for the study of the muscarinic acetylcholine receptor (mAChR) with PET. Two synthetic approaches, a 2-step reductive alkylation procedure and a 4-step alkylation approach, were investigated. The alkylation approach with higher overall radiochemical yields was used to prepare 2- and 4-FDEX for biodistribution studies. The overall synthesis time for both compounds was 2.5 h and the overall radiochemical yield at end-of-synthesis was 12%. The specific activity was found to be greater than 600 mCi/mumol. Biodistribution studies of 2-FDEX in rats produced striatum-to-cerebellum and cortex-to-cerebellum ratios of 8.6 +/- 1.1 and 8.4 +/- 1.0 at 1 h after injection, and 12.1 +/- 2.1 and 10.7 +/- 2.2 at 3 h, respectively. Substantial radioactivity detected in bone indicated the in vivo defluorination of 2-FDEX. The striatum-to-cerebellum ratio for 4-FDEX was slightly lower at 1 h (5.9 +/- 0.9) but equally high at 3 h (12.3 +/- 2.0) when compared to 2-FDEX, and there was little bone uptake. The uptake of both 2-FDEX and 4-FDEX into mAChR rich brain regions (e.g. striatum, cortex) was blocked by a dose of dexetimide (5 mg/kg). Our results suggest 4-FDEX is a potential PET agent for study mAChR in vivo.
Acetylcholine↗
Evaluation of two new bifunctional chelates for radiolabeling a parathyroid-specific monoclonal antibody with In-111.
BB5-G1, a monoclonal antibody specific for human parathyroid cell membrane antigen was conjugated with two new ligands, BrMe2HBED and Br phi HBED and radiolabeled with 111In. We have compared the biodistribution of 111In-labeled BB5 using the new ligands to conventionally labeled (125I-labeled and 111In-DTPA-labeled) BB5 in a nude mouse model. Both 111In-BrMe2HBED-BB5 and 111In-Br phi HBED-BB5 attained high parathyroid-to-blood and parathyroid-to-muscle ratios by 72-96 h. 111In-Br phi HBED-BB5 showed lower %ID/g than 111In-BrMe2HBED-BB5 in the clearance organs, the liver and kidney; renal activity had cleared significantly by 120 h. This work suggests that 111In-Br phi HBED-BB5 offers improved in vitro behavior and may be useful as a radiopharmaceutical for localizing parathyroid tissue.
Animals↗
TMPHPG: a lipophilic derivative of EHPG for iron, gallium-68 and indium-111 hepatobiliary clearance.
TMPHPG (N,N'-trimethylenebis[2-(2-hydroxy-3,5-dimethylphenyl)glycine]) is a derivative of the ligand EHPG (ethylenebis[2-(o-hydroxyphenyl)glycine]) but is more lipophilic and had been synthesized to increase hepatobiliary clearance. 59Fe(III), 68Ga(III) and 111In(III) complexes of this ligand have been investigated as potential imaging agents for MRI, PET and SPECT, respectively. Metal-dependent differences in blood and liver clearance in mature rats have been evaluated.
Animals↗
Targeting radiopharmaceuticals--II. Evaluation of new trivalent metal complexes with different overall charges.
Three new multidentate ligands designed to have high affinity for Ga3+, In3+ and Fe3+ have been synthesized. N-(2-hydroxybenzyl)-N'-pyridoxylethylenediamine-N,N'-diacetic acid (HBPLED), N-(2-hydroxy-3,5-dimethylbenzyl)-N'-(3-hydroxy-1,2,5-trimethyl-4- pyridylmethyl)ethylenediamine-N,N'-diacetic acid (Me4HBPLED) and N,N'-bis(3-hydroxy-1,2,5-trimethyl-4-pyridylmethyl) ethylenediamine-N,N'-diacetic acid (DMPLED). These ligands give metal-ligand (M-L) complexes with (M = Ga3+, In3+, Fe3+) overall charges of -1.0 and +1, respectively. The 67Ga, 68Ga and 111In complexes of each of the three ligands and the 59Fe complex of Me4HBPLED were prepared, characterized and their biodistributions determined in rats after intravenous injection. Despite the differences in overall charge, the biological behavior of all three 111In complexes were similar, in that the radioactivity cleared rapidly via the kidney. The biodistributions of the 68Ga and 67Ga complexes were comparable to that of the 111In complex counterpart. Also, the 59Fe-Me4HBPLED biodistribution was not significantly different from those of the 68Ga- and 111In-Me4HBPLED. The renal clearance rate seems insensitive to the overall M-L charge; suggesting that the hydrophilic periphery of the ligand rather than the overall molecular charge determines the biological fate (with respect to renal clearance).
Animals↗
Disabling postural hypotension complicating diabetic autonomic neuropathy.
A 35-year-old Type 1 diabetic man with severe disabling postural hypotension was studied for physiological abnormalities, precipitating factors, and effect of current treatment. A 24-h blood pressure profile indicated a diurnal variation in systolic blood pressure with the lowest values recorded between 0100 and 0600 h, during which the patient often lost consciousness on standing (mean standing systolic pressure 78 mmHg at night vs 105 mmHg in the afternoon, p less than 0.001). Food induced a profound fall in systolic pressure, both while supine and while standing erect. The systolic pressure fall during euglycaemia was 49 mmHg vs 3 mmHg during hypoglycaemia. Plasma noradrenaline and adrenaline levels were low during euglycaemia, but increased during hypoglycaemia. Therapeutic manoeuvres aimed at increasing heart rate (by atrial tachypacing) and reducing the peripheral pooling of blood (vasoconstricting drugs and gravity suit), together with the somatostatin analogue octreotide, proved ineffective. These observations demonstrate the phenomenon of post-prandial exacerbation of postural hypotension in a Type 1 diabetic patient, and indicate that despite failure of conventional methods of treatment, hypoglycaemia increased plasma catecholamines and was effective in abolishing the blood pressure fall on standing.
Adult↗
The effects of naloxone on the cardiovascular and respiratory effects of centrally administered corticotrophin releasing factor in conscious rabbits.
1. The effects of intracerebroventricular (i.c.v.) and intracisternal (i.c.) administration of corticotrophin releasing factor (CRF) (0.5 nmol kg-1) were examined in conscious rabbits. The effect of opioid receptor antagonism was examined to determine whether the responses to CRF were mediated by endogenous opioid peptides. 2. After i.c.v. CRF there was a rise in mean arterial pressure (MAP), heart rate (HR), plasma noradrenaline and adrenaline, and increased behavioural activity. Respiration rate increased, PaCO2 fell, but PaO2 was unchanged. 3. The pressor and behavioural effects of i.c.v. CRF were unaltered by high doses of intravenous naloxone (9 mumols kg-1 bolus followed by 9 mumols kg-1 min-1 infusion); these effects of CRF were also not prevented by double this dose of naloxone. Naloxone attenuated the CRF-induced tachycardia, blocked the increase in respiration rate and increased the fall in PaCO2. 4. After i.c. CRF (0.5 nmol kg-1) there were similar changes in MAP, HR, plasma catecholamines, respiration and behaviour. 5. These results indicate that in conscious rabbits the pressor effects of i.c.v. CRF are not mediated by endogenous opioid peptides. The finding that the effects of CRF were similar after i.c.v. and i.c. administration suggests that these responses may result from actions on brainstem rather than periventricular sites.
Animals↗
The pressor response to central administration of beta-endorphin results from a centrally mediated increase in noradrenaline release and adrenaline secretion.
1. The effects of intracerebroventricular (i.c.v.) and intracisternal (i.c.) administration of beta-endorphin (0.01, 0.1 and 1.0 nmol kg-1) were examined in conscious rabbits. 2. After i.c.v. beta-endorphin, mean arterial pressure (MAP) increased, heart rate (HR) fell, plasma noradrenaline, adrenaline and glucose increased and there was a rise in PaCO2 and fall in PaO2; these effects were reversed by intravenous (i.v.) naloxone (300 nmol kg-1). 3. A combination of prazosin (2 mg kg-1) and yohimbine (1 mg kg-1), given i.v., prevented the rise in MAP induced by i.c.v. beta-endorphin. 4. After i.c. beta-endorphin, MAP, HR and plasma catecholamines were not significantly altered but there was a similar degree of respiratory depression. 5. Clonidine (1.0 micrograms kg-1, i.c.) reduced MAP and HR; these effects were not blocked by i.v. naloxone (6 mumol kg-1). 6. These results demonstrate that beta-endorphin acts centrally, probably mainly on periventricular mu-opioid receptors, to increase adrenaline secretion and sympathetic nerve activity leading to alpha-adrenoceptor-mediated vasoconstriction. The respiratory depression is probably mediated by brainstem mu-receptors. 7. A role for beta-endorphin in the central hypotensive action of alpha 2-adrenoceptor agonists was opposed by finding that opioid receptor antagonism with naloxone did not block the effects of clonidine.
Animals↗
The influence of food on postural hypotension in three groups with chronic autonomic failure--clinical and therapeutic implications.
The effect of a balanced liquid meal on supine and postural blood pressure (BP) responses was investigated in three groups of patients with chronic autonomic failure; 10 with associated neurological impairment (multiple system atrophy (MSA), Shy-Drager syndrome) and seven without (of which five had pure autonomic failure (PAF); and two had a deficiency of the enzyme dopamine beta hydroxylase, DBH-deficiency). All had marked postural hypotension. Subjects with normal autonomic function were also studied. In MSA and PAF food lowered supine BP substantially, with a more rapid and greater fall in PAF. After food, the levels of BP reached were considerably lower because of the reduced supine BP and many had to be returned to the horizontal position earlier than before. Ingestion of a similar volume of water alone had no effect in MSA or PAF. In DBH deficiency, food had variable but minimal effects on BP while supine and during head-up tilt. In subjects with normal autonomic function food did not affect BP. The BP responses to food thus varied in the three groups with chronic autonomic failure. The influence of food on both supine and postural BP therefore should be considered in the clinical and laboratory assessment of autonomic dysfunction and in relation to therapeutic approaches, designed to alleviate postural hypotension.
Adult↗
Hemodynamic and neurohormonal effects of clonidine in patients with preganglionic and postganglionic sympathetic lesions. Evidence for a central sympatholytic action.
BACKGROUND: Clonidine, a partial presynaptic and postsynaptic alpha-adrenoceptor agonist, has been shown to lower blood pressure in normal subjects but not in tetraplegics; however, the mechanisms of this action have not been elucidated. METHODS AND RESULTS: The hemodynamic and hormonal basis of the hypotensive action of clonidine was investigated in tetraplegics with complete cervical spinal cord transection and preganglionic sympathetic denervation, in patients with unilateral brachial plexus injury and postganglionic sympathetic denervation, and in normal subjects. In normal subjects, the fall in blood pressure after clonidine infusion was accompanied by a reduction in cardiac output that was predominantly due to a fall in stroke volume and in heart rate. The lack of fall in blood pressure, cardiac output, and stroke volume in tetraplegics indicates that these effects are exerted at a supraspinal level and require intact descending sympathetic pathways. After clonidine infusion, digital skin vasodilatation occurred in normal subjects, in the innervated but not the denervated limb of patients with unilateral brachial plexus injury, and in tetraplegics, indicating that this response is due to the central sympatholytic effect of clonidine. Plasma norepinephrine was much lower in tetraplegics compared with normal subjects, and after clonidine infusion, it fell substantially in normal subjects alone. Plasma renin activity did not change. Bladder stimulation in tetraplegics resulted in a rise in blood pressure and vasoconstriction in digital skin vessels. The inability of clonidine to significantly reduce or abolish the pressor and digital vasoconstrictor responses after bladder stimulation in tetraplegics indicates that clonidine does not exert a major effect on spinal preganglionic neurons or peripheral presynaptic alpha 2-adrenoceptors. CONCLUSIONS: Therefore, clonidine is a suitable drug for use in analyzing the central supraspinal levels of control in varying circulatory disorders, such as hypertension and postural hypotension.
Adolescent↗
Management of hypertension by reduction in sympathetic activity.
The sympathetic nervous system may initiate or maintain hypertension, and a range of approaches that reduce sympathetic activity is often of value in management. These may include nonpharmacological methods, such as the various forms of behavioral therapy (e.g., meditation, relaxation, and biofeedback techniques); weight reduction and avoidance of particular foods and agents that stimulate sympathetic activity (including caffeine and alcohol), and regular physical exercise. Pharmacological therapy includes centrally acting drugs such as alpha-methyldopa, clonidine, and reserpine; ganglionic blockers such as hexamethonium; agents acting on sympathetic nerve terminals such as guanethidine and debrisoquine; and drugs that may act at multiple sites, such as the beta-adrenergic blockers. The role of reducing sympathetic activity in the current management of hypertension and its complications is considered in this overview.
Behavior Therapy↗
Postprandial hypotension. Pathophysiological mechanisms and clinical implications in different disorders.
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Autonomic Nervous System↗
Role of sympathetic efferent nerves in blood pressure regulation and in hypertension.
This article presents some aspects of the role of sympathetic efferent nerves in the regulation of blood pressure in humans. Lessons have been learned from disorders that cause either sympathetic underactivity or overactivity. In chronic autonomic failure, pressor stimuli (mental arithmetic, isometric exercise, or cold) are unable to raise blood pressure, whereas stimuli that normally activate sympathetic efferent nerves to maintain blood pressure (head-up tilt, exercise, and food ingestion) can cause marked hypotension. Recognition of specific defects, such as the inability to synthesize norepinephrine in isolated dopamine beta-hydroxylase deficiency, suggests that sympathetic nerves may influence blood pressure regulation through nonadrenergic mechanisms (dopamine, neuropeptides, and purines). Tetraplegic patients with high cervical cord transection also have sympathetic impairment and postural hypotension, but this is less of a clinical problem because of compensatory hormonal and other mechanisms. Tetraplegic patients are unique as they also may have severe paroxysmal hypertension because of increased spinal sympathetic reflex activity. The pathophysiological mechanisms responsible for this exaggerated response include changes in postsynaptic adrenergic receptor numbers and their sensitivity, the actions of nonadrenergic cotransmitters, and the lack of sympathoneural pathways from the brain that are severed by the lesion. Finally, the putative role of the sympathetic nervous system in hypertension with unilateral renal artery stenosis, which initially is humorally mediated, is discussed. The centrally acting sympatholytic agent clonidine is effective in lowering blood pressure in renovascular hypertension independently of humoral factors when multiple agents have failed.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Positron emission tomography. Present status and future prospectives.
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Humans↗
Superior mesenteric artery vascular resistance is higher in hypertensives and is lowered by clonidine.
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Adult↗
Positron tomographic assessment of 16 alpha-[18F] fluoro-17 beta-estradiol uptake in metastatic breast carcinoma.
The positron-emitting estrogenic steroid 16 alpha-[18F]fluoro-17 beta-estradiol (FES) has been shown to exhibit selective uptake in primary breast carcinomas; the uptake of tracer by positron emission tomography (PET) is strongly correlated with the tumor estrogen-receptor concentration. We have now extended the use of this radiopharmaceutical for imaging of metastases of breast carcinoma by PET in 16 patients with clinical or radiographic evidence of metastatic disease. Increased uptake of FES was identified on PET images in 53 of 57 metastatic lesions (93%); only two apparent false-positive foci of FES uptake were seen. In seven of the patients, evaluable PET studies were obtained both before and after initiation of antiestrogen therapy. In all cases, there was a decrease in FES uptake in the tumor deposits after initiation of antiestrogen therapy, and the mean (+/- standard deviation) uptake decreased from 2.22 (+/- 1.23) to 0.80 (+/- 0.42) x 10(3)+ dose/ml. These results indicate that PET with FES has high sensitivity and specificity for detecting metastatic breast carcinoma and provide additional confirmatory evidence that the tumor uptake of this ligand is a receptor-mediated process.
Breast Neoplasms↗
Positron-labeled angiotensin-converting enzyme (ACE) inhibitor: fluorine-18-fluorocaptopril. Probing the ACE activity in vivo by positron emission tomography.
To evaluate the feasibility of probing the distribution of angiotensin-converting enzyme (ACE) in vivo using positron emission tomography (PET), 4-cis-[18F]fluorocaptopril (18FCAP) was prepared by the reaction of the triflate 2 with K18F/Kryptofix 222 in MeCN followed by hydrolysis (2 N NaOH). The synthesis time was 1 hr with an average radiochemical yield (EOS) of 12% and a specific activity of greater than 300 Ci/mmol. In vivo biodistribution in rats at 30 min after administration showed high uptakes into organs known to have high ACE concentration (lung, kidney and aorta) and faster clearance of 18FCAP for lung and kidney, compared to the clearance from the aorta. When different amounts of unlabeled 4-cis-fluorocaptopril (SQ 25750) were coinjected in rats, a dose of greater than 5 micrograms/kg decreased the lung uptake by one-half while only 1 microgram/kg decreased the kidney uptake by one-half. In general, the binding in the four tissues studied was saturable with the expected capacity. 18FCAP was administered to a human and displaceable uptake observed in the lung and kidney. The results demonstrate the feasibility of probing ACE in vivo using PET.
Angiotensin-Converting Enzyme Inhibitors↗