Regional Distribution Of Radioactivity Research Articles

Noninvasive evaluation of nicotinic acetylcholine receptor availability in mouse brain using single-photon emission computed tomography with [123I]5IA

IntroductionNicotinic acetylcholine receptors (nAChRs) are of great interest because they are implicated in higher brain functions. Nuclear medical imaging is one of the useful techniques for noninvasive evaluation of physiological and pathological function in living subjects. Recent progress in nuclear medical imaging modalities enables the clear visualization of the organs of small rodents. Thus, translational research using nuclear medical imaging in transgenic mice has become possible and helps to elucidate human disease pathology. However, imaging of α4β2 nAChRs in the mouse brain has not yet been performed. The purpose of this study was to assess the feasibility of single-photon emission computed tomography (SPECT) with 5-[123I]iodo-3-[2(S)-azetidinylmethoxy]pyridine ([123I]5IA) for evaluating α4β2 nAChR availability in the mouse brain. MethodsA 60-min dynamic SPECT imaging session of α4β2 nAChRs in the mouse brain was performed. The regional distribution of radioactivity in the SPECT images was compared to the density of α4β2 nAChRs measured in an identical mouse. Alteration of nAChR density in the brains of Tg2576 mice was also evaluated. ResultsThe mouse brain was clearly visualized by [123I]5IA-SPECT and probe accumulation was significantly inhibited by pretreatment with (−)-nicotine. The regional distribution of radioactivity in SPECT images showed a significant positive correlation with α4β2 nAChR density measured in an identical mouse brain. Moreover, [123I]5IA-SPECT was able to detect the up-regulation of α4β2 nAChRs in the brains of Tg2576 transgenic mice. Conclusions[123I]5IA-SPECT imaging would be a promising tool for evaluating α4β2 nAChR availability in the mouse brain and may be useful in translational research focused on nAChR-related diseases.

Evaluation of serotonin 5-HT1Areceptors in rodent models using [18F]mefway PET

Serotonin 5-HT(1A) receptors have been investigated in various CNS disorders, including epilepsy, mood disorders, and neurodegeneration. [¹⁸F]Mefway (N-{2-[4-(2'-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(cis/trans-4'-[¹⁸F]fluoromethylcyclohexane)-carboxamide) has been developed as a suitable positron emission tomography (PET) imaging agent for these receptors. We have now evaluated the suitability of [¹⁸F]trans-mefway in rat and mouse models using PET and computerized tomography (CT) imaging and corroborated with ex vivo and in vitro autoradiographic studies. Normal Sprague-Dawley rats and Balb/C mice were used for PET/CT imaging using intravenously injected [¹⁸F]trans-mefway. Brain PET data were coregistered with rat and mouse magnetic resonance imaging template and regional distribution of radioactivity was quantitated. Selected animals were used for ex vivo autoradiographic studies to confirm regional brain distribution and quantitative measures of binding, using brain region to cerebellum ratios. Binding affinity of trans-mefway and WAY-100635 was measured in rat brain homogenates. Distribution of [¹⁸F]trans-4-fluoromethylcyclohexane carboxylate ([¹⁸F]FMCHA), a major metabolite of [¹⁸F] trans-mefway, was assessed in the rat by PET/CT. The inhibition constant, K(i) for trans-mefway was 0.84 nM and that for WAY-100635 was 1.07 nM. Rapid brain uptake of [¹⁸F]trans-mefway was observed in all rat brain regions and clearance from cerebellum was fast and was used as a reference region in all studies. Distribution of [¹⁸F]trans-mefway in various brain regions was consistent in PET and in vitro studies. The dorsal raphe was visualized and quantified in the rat PET but identification in the mouse was difficult. The rank order of binding to the various brain regions was hippocampus > frontal cortex > anterior cingulate cortex > lateral septal nuclei > dorsal raphe nuclei. [¹⁸F]trans-Mefway appears to be an effective 5-HT(1A) receptor imaging agent in rodents for studies of various disease models.

Radiolabeling of the cannabinoid receptor agonist AZD1940 with carbon-11 and PET microdosing in non-human primate

N-(2-tert-butyl-1-((4,4-difluorocyclohexyl)methyl)-1H-benzo[d]imidazol-5-yl)ethanesulfonamide (AZD1940) is a candidate drug for treatment of neuropathic pain. As part of the preclinical evaluation of AZD1940, a microdosing study with positron emission tomography (PET) was conducted to assess brain exposure. AZD1940 was radiolabeled with carbon-11 in the benzimidazole moiety. The radioactive precursor, lithium [(11)C]pivalate was obtained via (11)C-carboxylation of tert-butyl lithium. The target compound, [(11)C]AZD1940, was in turn obtained by the microwave assisted reaction between lithium [(11)C]pivalate and the o-phenylene diamine analog of AZD1940 (N-(3-amino-4-((4,4-difluorocyclohexyl)methylamino)phenyl)ethanesulfonamide) in neat phosphorous oxychloride. A brain PET measurement was performed in cynomolgus monkey. The overall radiochemical yield of final formulated radiochemically pure (>99%) [(11)C]AZD1940 was 0.4% (uncorrected for decay) and the specific radioactivity was 13GBq/μmol at time of administration (58min after end of bombardment). After intravenous injection to cynomolgus monkey, the maximum concentration of radioactivity detected in the brain region of interest was 0.7% of the total injected radioactivity. The regional distribution of radioactivity within brain was homogenous. AZD1940 was radiolabelled with carbon-11 and its brain exposure, assessed using PET, was relatively low in comparison to peripheral organ exposure.

Positron emission tomography inter-scanner differences in dopamine D2 receptor binding measured with [11C]FLB457

It is well known that the positron emission tomography (PET) system is subject to inter-scanner differences of regional radioactivity distribution. In the present study, the effect of inter-scanner difference of regional radioactivity on estimated binding potential (BP(ND)) of [¹¹C]FLB457 using the simplified reference tissue model (SRTM) was investigated. Each of the 11 subjects was given two PET scans using [¹¹C]FLB457, one each with both SET-3000 GCT/X (Shimadzu) and with ECAT EXACT HR+ (Siemens/CTI). In order to assess regional differences between the two scanners, estimated BP(ND) values in six volumes of interest (VOIs) by SRTM method were compared in both individual PET space and anatomical template space after anatomical normalization. Statistical voxel-by-voxel paired t test of BP(ND) images between SET-3000 GCT/X and ECAT EXACT HR+ was also performed. Shapes of time-activity curves of the two PET scanners were slightly different in each VOI, with estimated BP(ND) values from ECAT EXACT HR+ appearing greater in the cerebral cortical regions and thalamus than that of SET-3000 GCT/X in both individual PET space and anatomical template space after anatomical normalization. Statistical voxel-by-voxel analysis showed similar tendency to BP(ND) value estimation, with greater BP(ND) values from ECAT EXACT HR+ than from SET-3000 GCT/X. We demonstrated the inter-scanner differences in dopamine D(2) receptor binding measured with [¹¹C]FLB457. In particular, statistically significant differences of BP(ND) in certain regions were observed between two PET scanners, despite the subject groups being the same. Our results suggest that we reconsider the effect of the scanner model on the measurement of receptor binding.

In Vivo Evaluation of Limiting Brain Penetration of Probes for α2C-Adrenoceptor Using Small-Animal Positron Emission Tomography

To evaluate in vivo brain penetration of α(2C)-adrenoceptor (α(2C)-AR) antagonists as a therapeutic agent, we synthesized two new (11)C-labeled selective α(2C)-AR antagonists 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-2-aryl-7-methoxybenzofuran ([(11)C]MBF) and acridin-9-yl-[4-(4-methylpiperazin-1-yl)phenyl]amine ([(11)C]JP-1302) as α(2C)-AR-selective positron emission tomography (PET) probes. The radiochemical yield, specific activity, and radiochemical purity of these probes was appropriate for injection. To evaluate whether the brain penetration of these probes is related to the function of two major drug efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), we performed PET studies using wild-type and P-gp/Bcrp knockout mice. In wild-type mice, the radioactivity level after injection with [(11)C]MBF initially increased and effluxed immediately from the brain, whereas that with [(11)C]JP-1302 was distributed throughout the brain. However, the regional distribution of radioactivity after injection with [(11)C]JP-1302 in the brain was different from that of α(2C)-ARs. In P-gp/Bcrp knockout mice, uptake of [(11)C]MBF was approximately 3.7-fold higher and that of [(11)C]JP-1302 was approximately 1.6-fold higher than those in wild-type mice. These results indicate that brain penetration of the two PET probes was affected by modulation of P-gp and Bcrp functions.

18F-ZW-104: A New Radioligand for Imaging Neuronal Nicotinic Acetylcholine Receptors—In Vitro Binding Properties and PET Studies in Baboons

An extensive series of radioligands has been developed for imaging central nicotinic acetylcholine receptors (nAChRs) with PET. Two halogeno-derivatives of A-85380 are being used in humans. Nevertheless, these derivatives still display too-slow brain kinetics and low signal-to-noise ratio. A novel nAChR radioligand, 5-(6-fluorohexyn-1-yl)-3-[2(S)-2-azetidinylmethoxy]pyridine (ZW-104), was characterized in vitro using competition binding assays (nAChR subtypes heterologously expressed in HEK 293 cells and in native alpha4beta2 nAChRs from rat brain). (18)F-ZW-104 was prepared as follows: no-carrier-added nucleophilic aliphatic radiofluorination of the corresponding N-Boc-protected tosyloxy derivative 5-(6-tosyloxyhexyn-1-yl)-3-[2(S)-(N-(tert-butoxycarbonyl))-2-azetidinylmethoxy] pyridine) with the activated 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[8,8,8]hexacosane (K-(18)F-F-Kryptofix 222 [K(222)] complex), followed by quantitative trifluoroacetic acid-induced removal of the N-Boc protective group. (18)F-ZW-104 was then studied in baboons using PET. ZW-104 showed high binding affinities for rat alpha4beta2 nAChRs (K(i), 0.2 nM) and other subtypes containing the beta2 subunit but much lower affinities for rat alpha3beta4 nAChRs (K(i), 5,500 nM) and other subtypes containing the beta4 subunit. The regional radioactivity distribution in the baboon brain matched that of the alpha4beta2 nAChR, which was similar to that of 2-(18)F-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-(18)F-A-85380), a radioligand used in humans. Comparison between (18)F-ZW-104 and 2-(18)F-A-85380 demonstrated better in vivo binding properties of the new radioligand: a substantially greater amount of radioactivity accumulated in the brain, and the occurrence of peak uptake in the thalamus was earlier than that of 2-(18)F-A-85380 and was followed by washout. Distribution volume values in different brain regions were 2-fold higher for (18)F-ZW-104 than for 2-(18)F-A-85380. Displacement by nicotine or unlabeled ZW-104 demonstrated a lower nonspecific binding than that of 2-F-A-85380. These results suggest that (18)F-ZW-104 is a promising PET radioligand for studying nAChRs containing the beta2 subunits in humans.

Influence of P-glycoprotein on brain uptake of [ 18F]MPPF in rats

The aim of this study was to determine if the brain uptake of 4-(2′-methoxyphenyl)-1-[2′-( N-2″-pyridinyl)- p-[ 18F]fluorobenzamido]ethylpiperazine ([ 18F]MPPF), a radioligand for the imaging of 5-HT 1A receptors, is influenced by the action of P-glycoprotein. Anesthetized male Wistar rats were injected i.v. with the 5-HT 1A receptor antagonist [ 18F]MPPF (2 MBq, S.A.>110 TBq/mmol) after treatment with saline (controls) or with the 5-HT 1A receptor antagonist 1-(2′-methoxyphenyl)-4-[4-(2-phtalimido)butyl]piperazine (NAN-190) (2.5 mg/kg i.v.). After 60 min, the animals were sacrificed and 13 areas of the brain were dissected for ex vivo gamma counting. The regional distribution of radioactivity was also assessed in brain slices using a storage phosphor system. Modulation of P-glycoprotein was achieved by injection of cyclosporin A (50 mg/kg) 30 min prior to injection of [ 18F]MPPF. The distribution of 18F-derived radioactivity corresponded to regional 5-HT 1A receptor density as known from autoradiography. Modulation of P-glycoprotein with cyclosporin A caused a 5- to 10-fold increase in the uptake of [ 18F]MPPF. Tissue/cerebellum ratios in the brain correlated with receptor densities determined by in vitro autoradiography. Measurements of plasma radioactivity showed that the increased brain uptake of [ 18F]MPPF is partially due to a rise in ligand delivery after treatment with cyclosporin A (area under the curve, AUC, increased by a factor of 1.8). Biodistribution experiments in wild type and mdr1a(−/−) knockout mice confirmed that [ 18F]MPPF is a substrate for P-glycoprotein.

Radioiodinated (—)-2-[4-(3-iodophenyl) piperidino] cyclohexanol

We synthesized the (-)-enantiomer of radioiodinated 2-[4-(3-iodophenyl) piperidino] cyclohexanol ((-)-[125I]-m-iodovesamicol [(-)-[125I]mIV]) and evaluated its in vivo binding specificity and affinity for the vesamicol receptor in the rat brain. Significant amounts (approximately 3% of the injected dose) of (-)-mIV accumulated and retention was prolonged. The accumulation of (-)-[125I]mIV in the brain was significantly reduced by the pre- and post-administration of unlabelled vesamicol (0.5 mumol kg -1). Blocking and displacement studies in vivo showed that the binding affinity of (-)-[125I]mIV for the vesamicol receptor was very high, but that for other receptors was very low. Autoradiographic studies showed that the regional distribution of radioactivity, as revealed by coronal sections of the rat brain, was similar for both (-)-[125I]mIV and (-)-[3H]vesamicol. The results demonstrated that the characteristics of (-)-[125I]mIV for binding sites in rat brain were similar in vivo and in vitro. Radioiodinated (-)-mIV may potentially be useful for studying presynaptic cholinergic neurons in the brain.

Opioid receptor imaging and displacement studies with [6- O-[ 11C]methyl]buprenorphine in baboon brain

Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an analgesic and in the treatment of opiate addiction. We have used [6- O-[ 11C]methyl]buprenorphine ([ 11C]BPN) to measure the regional distribution in baboon brain, the test-retest stability of repeated studies in the same animal, the displacement of the labeled drug by naloxone in vivo, and the tissue distribution in mice. The regional distribution of radioactivity in baboon brain determined with PET was striatum > thalamus > cingulate gyrus > frontal cortex > parietal cortex > occipital cortex > cerebellum. This distribution corresponded to opiate receptor density and to previously published data (37). The tracer uptake in adult female baboons showed no significant variation in serial scans in the same baboon with no intervention in the same scanning session. HPLC analysis of baboon plasma showed the presence of labeled metabolites with 92% ± 2.2% and 43% ± 14.4% of the intact tracer remaining at 5 and 30 min, respectively. Naloxone, an opiate receptor antagonist, administered 30–40 min after tracer injection at a dose of 1.0 mg/kg i.v., reduced [ 11C]BPN binding in thalamus, striatum, cingulate gyrus, and frontal cortex to values 0.25 to 0.60 of that with no intervention. There were minimal (<15%) effects on cerebellum. Naloxone treatment significantly reduced the slope of the Patlak plot in receptor-containing regions. These results demonstrate that [ 11C]BPN can be displaced by naloxone in vivo, and they affirm the feasibility of using this tracer and displacement methodology for short-term kinetics studies with PET. Mouse tissue distribution data were used to estimate the radiation dosimetry to humans. The critical organ was the small intestine, with a radiation dose estimate to humans of 117 nrad/mCi.

In vivo labeling of neuronal nicotinic acetylcholine receptors with radiolabeled isomers of norchloroepibatidine.

In vitro binding studies have shown that epibatidine and its norchloro analogues have high affinities for the cholinergic nicotinic receptor. In this study, the in vivo binding characteristics of [3H](+)norchloroepibatidine (NCEPB) and [3H](-)NCEPB in mice were examined. After injection of [3H](+)NCEPB, radioactivity levels in all brain regions examined increased and then decreased, with different regions accumulating different levels of radioactivity. The regional distribution of radioactivity at later times paralleled the distribution of nicotinic receptor binding in vitro. The ratio of radioactivity in the superior colliculus to that in the cerebellum, a reflection or estimate of total: non-specific binding, was strikingly high at 8 h (about 35). Drugs known to bind to nicotinic receptors reduced [3H](+)NCEPB binding, while atropine and spiperone, muscarinic and dopaminergic drugs respectively, did not. [3H](-)NCEPB had a similar regional distribution to [3H](+)NCEPB. Pretreatment with increasing doses of non-radioactive (-)NCEPB resulted in saturation of in vivo binding of [3H](-)NCEPB. These data indicate that [3H](+) and (-)NCEPB are useful in vivo binding ligands for the cholinergic nicotinic receptor.

In vivo labeling of sigma receptors in mouse brain with [3H]4‐phenyl‐1‐(4‐phenylbutyl)piperidine

4-Phenyl-1-(4-phenylbutyl)piperidine (4-PPBP) is a very potent ligand for sigma (Sigma) receptors. The present study was undertaken to evaluate [3H]4-PPBP as a radioligand for in vivo labeling of cerebral sigma receptors. After intravenous administration of [3H]4-PPBP to mice, there is high uptake of radioactivity in the brain. The regional distribution of radioactivity in the brain 2 h after intravenous injection of [3H]4-PPBP parallels the in vitro binding of the radioligand in rat brain (pons/medulla > cerebellum > or = prefrontal cortex > or = parietal cortex > hypothalamus > olfactory tubercle > or = thalamus > hippocampus > striatum). Pretreatment with haloperidol (2 mg/kg) significantly decreases the radioactivity measured in the brain 30-120 min after injection of [3H]4-PPBP. Pretreatment with unlabeled 4-PPBP or ifenprodil also significantly decreases radioactivity in the brain 2 h after injection of [3H]4-PPBP, in a dose-dependent manner. The in vivo binding of [3H]4-PPBP in the brain also is significantly inhibited by SL 82.0715, BMY 14802, 1,3-di-o-tolylguanidine (DTG), and (+)-enantiomers of pentazocine, SKF 10,047, and 3-PPP, but not by the corresponding (-)-enantiomers, consistent with stereoselectivity of inhibition obtained in in vitro binding studies. In contrast, pretreatment with dizocilpine and spiperone does not inhibit in vivo binding of [3H]4-PPBP. The results indicate that [3H]4-PPBP would be a suitable radioligand for in vivo labeling of sigma receptors in brain.

Uptake and regional distribution of (+)-(R)- and (-)-(S)-N-[methyl-11C]-nicotine in the brains of rhesus monkey. An attempt to study nicotinic receptors in vivo.

N-[methyl-11C] nicotine (11C-nicotine) was given intravenously to monkeys and the uptake and regional distribution of radioactivity was followed in the brain using positron emission tomography (PET). The 11C-radioactivity in the brain peaked within 1-2 min and then rapidly declined. Pretreatment with unlabelled nicotine (10 micrograms/kg) reduced the uptake of 11C-radioactivity to the brain by 30%. The uptake of radioactivity was higher following (+)11C-nicotine than (-)11C-nicotine. Both enantiomers were distributed in a similar manner within the brain. When animals were infused with a peripheral nicotinic blocker (trimetaphan) the uptake of radioactivity to the brain was lower following (+)11C-nicotine compared to (-)11C-nicotine. The amount of radioactivity was high in the occipital cortex, thalamus, intermediate in the frontal cortex and low in white matter in (-)11C injected monkeys while no regional difference in distribution of 11C-radioactivity was observed after injection of (+)11C-nicotine.

Synthesis and evaluation of [ 11C]cyanoimipramine

[ 11C]Cyanoimipramine has been prepared by methylation of the desmethyl cyanoimipramine with [ 11C]methyl iodide. The chemically and radiochemically pure labelled product was obtained with a high specific activity (> 300 mCi/μmol). When 11C (or 3H)-cyanoimipramine was intravenously administered in mice, high accumulations were shown in brain and lung. Thirty minutes after injection of the tracer, differences were found in the radioactivity between the cerebral cortex and the cerebellum. The regional distribution of radioactivity in the rat brain 30 min after i.v. injection of [ 11C]cyanoimipramine was also examined, and the radioactivity was high in receptor rich areas (striatum, cerebral cortex etc.) but low in receptor poor area (cerebellum). The in vivo stability of [ 3H]cyanoimipramine was quite stable in the mouse brain for at least 30 min. Thirty minutes after injection, the radioactivity in the cerebral cortex of the carrier-added state was reduced as compared with the carrier-free state. Taken together, the in vivo specific binding of [ 3H]cyanoimipramine in the cerebral cortex was estimated at about 40–50% of the total radioactivity. Furthermore, the distribution of [ 3H]cyanoimipramine in the mice forced to swim was examined. Significant changes in the distribution of [ 3H]cyanoimipramine were observed in the cerebral cortex.

Localization of serotonin 5-HT2 receptors in living human brain by positron emission tomography using N1-([11C]-methyl)-2-Br-LSD.

N1-([11C]-Methyl)-2-Br-LSD ([11C]-MBL) has been developed as a positron emission tomography (PET) imaging agent for serotonin 5-HT2 receptors. In vitro receptor binding assays with nonradioactive MBL show high-affinity binding to serotonin 5-HT2 receptors (Ki = 0.5 nM), a secondary interaction of 8-fold lower affinity with dopamine D2 receptors, and low-affinity interactions with alpha 1-adrenergic as well as serotonin 5-HT1 receptors. Intravenous injection of [11C]-MBL in a baboon led to selective labeling of cortical regions that was markedly blocked by prior administration of ketanserin, a selective 5-HT2 receptor antagonist. Clinical trials with [11C]-MBL have been conducted in seven normal human volunteers, and the regional distribution of radioactivity in the brain was distinctly serotonergic. Labeling was highest in frontal, temporal, and parietal cortex with lower levels observed in caudate and putamen. The tracer rapidly washed from the cerebellum and the low levels of activity in this brain region were used to define nonspecific binding. The maximum specificity was reached between 30 and 60 minutes postinjection when frontal cortex to cerebellum ratios ranged from 1.7 for a 52-year-old male to 2.7 for a 30-year-old male. In agreement with previous studies, a trend towards lower ratios (lower serotonin 5-HT2 receptor levels) was observed in older volunteers. These studies indicate that [11C]-MBL is a selective radioligand that can be used to monitor serotonin 5-HT2 receptor densities in vivo in most regions of the human brain.

In vivo binding of N-n-propylnorapomorphine in the rat brain: Regional localization, quantification in striatum and lack of correlation with dopamine metabolism

The accumulation and retention of radioactivity in rat brain were studied after intravenous injection of the dopamine (DA) agonist [ 3H]N-n-propylnorapomorphine ([ 3H]NPA). Dose-dependent saturable accumulation of label was found in the striatum, nucleus accumbens and olfactory tubercle. DA agonists (apomorphine, N,N-dipropyl-5,6-ADTN) and antagonists (haloperidol, cis-flupenthixol) prevented this accumulation. Enhanced accumulation of radioactivity in the striatum was found after 6-OHDA lesions and short- and long-term treatment with reserpine. These results are an indication of specific NPA binding to presumably postsynaptically situated DA receptors. One hour after administration of the drug, the effect of NPA on striatal DA metabolism was not correlated with receptor saturation. Maximal numbers of in vivo NPA binding sites (about 30 and 22 pmol · g −1) in striatal tissue were calculated from independent measurements at 15 and 60 min after NPA injection. Regional distribution of radioactivity after a tracer dose of [ 3H]NPA was assessed in 35 brain areas and parts of the spinal cord. In addition to the already mentioned DA-rich areas receptor-specific NPA binding was also found in several other brain parts.

3H-Δ 9-tetrahydrocannabinol, 3H-cannabinol and 3H-cannabidiol: Penetration and regional distribution in rat brain

3H-Δ 9-Tetrahydrocannabinol ( 3H-Δ 9-THC), 3H-cannabidiol ( 3H-CBD) and 3H-cannabinol ( 3H-CBN) were administered (1 mg/kg) to male rats which were decapitated either 0.5, 1, 15, 30 or 90 min later. The plasma concentration was similar for all cannabinoids throughout the time course. After 5 min greater than 80% of the plasma radioactivity in each treatment was due to metabolites. Radioactivity rapidly entered brain after the administration of 3H-CBD, 3H-CBN, and 3H-Δ 9-THC. The concentrations of unchanged 3H-CBD and 3H-CBN in whole brain were higher than that of 3H-Δ 9-THC 5 min after administration. Regional distribution of radioactivity in the brain after 5 min was similar for all three cannabinoids, the only significant difference being in hypothalamus. Coadministration of 3H-Δ 9-THC with a five-fold excess of either CBD or Δ 9-THC did not produce any significant alteration in the levels of radioactivity in brain or plasma 5 min after their injection. The difference in behavioral activity of Δ 9-THC, CBD and CBN cannot be explained by penetrability or regional distribution in the brain.

Evidence for pituitary-brain transport of a behaviorally potent acth analog

Following intrapituitary injection of 3H-ACTH 4–9 analog, the radioactivity of various brain regions was determined in intact rats and in rats with the pituitary stalk cut one or eight days previously. The regional distribution of radioactivity in the brain was also investigated after intravenous and intrasellar administration. Intrasellar and intrapituitary administration resulted in significantly higher radioactivity levels in the brain than did intravenous injection of an equimolar dose of labeled peptide. Intrapituitary injection resulted in an uptake with clear regional differences and which was highest in the hypothalamus. Twenty four hours after stalk section the uptake of radioactivity in the hypothalamus, but not in other brain regions was markedly depressed. Hypothalamic uptake, however, was restored at eight days after stalk section. The results suggest a significant flow of radioactivity from the pituitary to the brain, particularly to the hypothalamus. Transport to the hypothalamus is presumably partly vascular via the stalk. Transport to other brain areas may occur via the cerebrospinal fluid, but a neural route cannot be excluded.

What is nuclear medicine all about?

The field of nuclear medicine, defined as the application of radioactive tracers to medical diagnosis and treatment, has progressed significantly over recent years. At one time, only measurements of the concentrations of the radioactive tracers or other chemicals in blood, urine or other biologic material could be obtained at various intervals after the administration of a tracer or chemical. Therefore, prior to development of radiation detectors that reveal the distribution of radioactive tracers within the body, the function of the body could be studied only as a whole. It now is possible to study both regional and total body function by using the many radioactive tracers available and suitable imaging devices. By using the short-lived tracers (which have improved the quality of the images and reduced the radiation dose to the patient) and the recently developed scintillation camera, rapid dynamic studies of the course of the tracers through regions of the body may be performed, so that both spatial and temporal resolution is obtained. The use of computers has added a new dimension to the field of nuclear medicine. It is possible to improve greatly the quality of the information obtained. As a result, the regional distribution of radioactivity can be quantified and the changes that take place over a period of time in serial studies evaluated. Thus using a variety of radioactive tracers, each measuring a specific function, we can construct a mosaic of quantitative measurements of regional function. In this way, nuclear medicine may develop a body of coherent knowledge and become a clinical science as well as a collection of useful technics.

Autoradiographic studies on the distribution of 3H-2,3,4-trimethoxy-beta-phenylethylamine in the mouse.

The regional distribution of radioactivity was studied in the brain and in other organs of the mouse by light microscopic autoradiography after injection of 3H-2,3,4-trimethoxy-beta-phenylethylamine (2,3,4,-TMPEA), a nonhallucinogenic isomer of mescaline. The distribution patterns were compared with biochemical and autoradiographic results obtained after 3H-mescaline. Although 2,3,4-TMPEA is rapidly deaminated compared to mescaline its distribution pattern in the brain is similar to that of mescaline at 1 h after injection. However, contrary to mescaline the radioactive labeling becomes more and more homogenously distributed in the brain with tiem. The distribution patterns in kidney, pancreas, adrenal, and spinal ganglia were also different from those observed after application of 3H-mescaline.

Radiogenic heat production in prebatholithic rocks of the central Sierra Nevada

Likely source material for the Sierra Nevada batholith is represented by exposures of Paleozoic rocks on the western flanks of the Sierra Nevada, Paleozoic sedimentary rocks in roof pendants east of the Sierran crest, and both Precambrian and Paleozoic rocks in the western portion of the Basin and Range province. The radiogenic heat production of these rocks has been calculated from γ-radiometric determinations of their U, Th, and K contents. The abundances of these radioisotopes in carbonate rocks are roughly an order of magnitude lower than those in adjacent siliceous sedimentary rocks; therefore, the radiogenic heat production in the Paleozoics depends mainly on the relative amounts of carbonate and siliceous material. Heat production varies from east to west, with weighted values (expressed in units of μcal/g yr) of 3.7 in Precambrian rocks of the Death Valley area, 3.5 in Paleozoics of the Inyo and White mountains, 3.8 in Paleozoic pendants, and 2.1 in rocks of the Calaveras formation on the western slope. A difference, similar to that in the Paleozoics, is observed between Mesozoic rocks exposed near the crest (4.4) and the Mesozoics of the western foothills (2.4). The geographic distribution of heat production matches (though not proportionally) that in the batholithic rocks. This suggests that there was a regional distribution of radioactivity in likely source material for the granitic rocks that now, strongly accentuated by the effects of erosion, is reflected in the batholith.