Silicon photodiodes with high photoconductive gain at room temperature.

Silicon photodiodes with high photoconductive gain are demonstrated. The photodiodes are fabricated in a complementary metal-oxide-semiconductor (CMOS)-compatible process. The typical room temperature responsivity at 940 nm is >20 A/W and the dark current density is ≈ 100 nA/cm2 at 5 V reverse bias, yielding a detectivity of ≈ 10(14) Jones. These photodiodes are good candidates for applications that require high detection sensitivity and low bias operation.

In vivo muscarinic cholinergic receptor imaging in human brain with [11C]scopolamine and positron emission tomography.

Cerebral muscarinic cholinergic receptors were imaged and regionally quantified in vivo in humans with the use of [11C]scopolamine and positron emission tomography. Previous studies in experimental animals have suggested the utility of radiolabeled scopolamine for in vivo measurements, on the bases of its maintained pharmacologic specificity following systemic administration and the exclusion of labeled metabolites from the brain. The present studies describe the cerebral distribution kinetics of [11C]scopolamine in normal subjects following intravenous injection. Scopolamine is initially delivered to brain in a perfusion-directed pattern. After 30 to 60 min, activity is lost preferentially from cerebral structures with low muscarinic receptor density including the cerebellum and thalamus. Activity continues to accumulate throughout a 2 h postinjection period in receptor-rich areas including cerebral cortex and the basal ganglia. The late regional concentration of [11C]scopolamine does not, however, accurately parallel known differences in muscarinic receptor numbers in these receptor-rich areas. Tracer kinetic analysis of the data, performed on the basis of a three-compartment model, provides receptor binding estimates in good agreement with prior in vitro measurements. Kinetic analysis confirms significant contributions of ligand delivery and extraction to the late distribution of [11C]scopolamine, reconciling the discrepancy between receptor levels and tracer concentration. Finally, a novel dual-isotope method for rapid chromatographic processing of arterial blood samples in radiotracer studies is presented. The combination of rapid chromatography and compartmental analysis of tracer distribution should have broad utility in future in vivo studies with short-lived radioligands.

Isolation of a human tissue-type plasminogen-activator genomic DNA clone and its expression in mouse L cells.

We have isolated a cDNA clone corresponding to a substantial portion of the human tissue-type plasminogen activator (t-PA) protein. It encodes almost all of the protein B chain and part of the 3' untranslated region. We have used this clone to screen bacteriophage lambda and cosmid libraries of human genomic DNA. Several related genomic clones were isolated. One of these, a cosmid clone, carried approx. 40 kb of human DNA. Mapping experiments indicate that the region containing the protein-coding exons is approx. 20 kb in length. The cosmid, containing the t-PA gene and the aminoglycosyl-3'-phosphotransferase dominant-selection marker, was introduced into mouse L cells. Approximately half of the transformants were shown to produce human t-PA. We demonstrated that the fibrinolytic t-PA activity could be specifically quenched by anti-t-PA antibody and that the recombinant t-PA was of similar size (by SDS-polyacrylamide gel electrophoresis) to the t-PA produced by the human Bowes melanoma cell line. Our results suggest that the cosmid clone carries the whole t-PA coding region together with the regulatory elements necessary for its expression.

Characterization of the 5-hydroxytryptamine2A receptor-activated cascade in rat C6 glioma cells.

We have investigated the identity and intracellular cascade of responses resulting from activation of the endogenous 5-hydroxytryptamine receptor in the C6 rat glioma cell line. Sequence analysis of reverse transcription-polymerase chain reaction products derived from C6 glioma cell messenger RNA revealed complete homology with a portion of the rat 5-hydroxytryptamine2A receptor. The binding of [3H]ketanserin to cell membranes demonstrated a significant correlation with the 5-hydroxytryptamine2A receptor in rat frontal cortex. On intact cells, 5-hydroxytryptamine stimulated a concentration-dependent increase in phosphatidyl inositide turnover and intracellular [Ca2+] mediated by 5-hydroxytryptamine2A receptors. In whole-cell patch-clamp recordings, 5-hydroxytryptamine induced an outward current mediated predominantly by K+ ions (reversal potential = -80 mV). Using caged molecules containing Ca2+ or inositol 1,4,5-trisphosphate in the patch electrode solution, we found that rapid photolytic release of Ca2+ and particularly inositol 1,4,5-trisphosphate within the cytosol induced an outward current with characteristics similar to those seen after application of 5-hydroxytryptamine. Comparison between differentiated and undifferentiated cells revealed significantly higher receptor density and maximal phosphoinositide response to 5-hydroxytryptamine in undifferentiated cells but the associated rise in [Ca2+]i and activation of an outward current was observed more frequently in differentiated cells. Prolonged exposure of the cells to 5-hydroxytryptamine led to a decrease in all responses and to the down-regulation of receptor number. We conclude that the rat C6 glioma cell expresses a 5-hydroxytryptamine2A receptor identical to that found in rat brain and that stimulation of the receptor in C6 cells leads to the activation of Ca2+ activated K+ channels via phosphoinositide hydrolysis and subsequent rise in cytosolic Ca2+ ion concentration. However, the contrasting effects of differentiation on receptor number and phosphoinositide response to 5-hydroxytryptamine compared to Ca2+ release and conductance change indicate that a complex relationship exists between the component parts of the receptor-activated cascade.

Thyroid carcinoma with high levels of function: treatment with (131)I.

UNLABELLED: In some patients with well-differentiated thyroid carcinoma, dosimetry is necessary to avoid toxicity from therapy and to guide prescription of the administered activity of radioiodine. METHODS: The presentations and courses of 2 patients exemplify the points. In the second patient, the clues to the need for dosimetry were the large size of the tumor and high circulating levels of thyroxine in the absence of exogenous hormone. The other patient manifested hyperthyroidism from stimulation of the tumors by thyroid-stimulating immunoglobulin. Dosimetry was performed by published methods. RESULTS: Dosimetry of radioactivity in the body and blood warned of increased irradiation per gigabecquerel of administered (131)I. In each patient, the tumors sequestered a substantial amount of administered (131)I and secreted (131)I-labeled hormones that circulated for days. In 1 patient, the blood time--activity curve was complex, making a broad range of predictions for irradiation to blood and bone marrow. Still, dosimetry gave information that helped to avoid severe toxicity. At, respectively, 1.85 and 2.2 GBq (131)I, initial treatments were relatively low. There was a modest escalation in subsequent administered activities. Leukopenia with neutropenia developed in each patient, and one had moderate thrombocytopenia and anemia, but toxicity appeared to be transient. Each patient had a marked increase in well-being and evidence of reduced tumor function and volume. CONCLUSION: Two patients with advanced, well-differentiated thyroid carcinoma illustrate the need for dosimetry to help prevent toxicity to normal tissues from therapeutic radioiodine. Conversion of radioiodide to circulating radiothyroxine by functioning carcinomas increases the absorbed radiation in normal tissues. Yet, dosimetric data acquired for 4 d or more may be insufficient for accurate calculations of absorbed radiation in blood. Guidelines suggested for avoiding toxicity are based on the circulating thyroxine concentrations, the presence of thyroid stimulators, the amount of radioactivity retained in the body at 48 h, and the general status of the patient.

Quantitative organ visualization using SPECT.

Quantitative organ visualization (QOV) was performed using single photon emission computed tomography (SPECT). Organ size was calculated from serial, contiguous ECT images taken through the organ of interest with image boundaries determined using a maximum directional gradient edge finding technique. Organ activity was calculated using ECT counts bounded by the directional gradient, imaging system efficiency, and imaging time. The technique used to perform QOV was evaluated using phantom studies, in vivo canine liver, spleen, bladder, and kidney studies, and in vivo human bladder studies. It was demonstrated that absolute organ activity and organ size could be determined with this system and total imaging time restricted to less than 45 min to an accuracy of about +/- 10% providing the minimum dimensions of the organ are greater than the FWHM of the imaging system and the total radioactivity within the organ of interest exceeds 15 nCi/cc for dog-sized torsos. In addition, effective half-lives of approximately 1.5 hr or greater could be determined.

Absorbed dose to the human adrenals from lodomethylnorcholesterol (I-131) "NP-59": concise communication.

During the past 2 years, adrenal uptake percentage values were measured in more than 40 patients, using an external counting technique. They suggest that the absorbed dose to the adrenals is significantly less than 150 rads/mCIi previously estimated using concentration values from animal adrenals. The measured combined uptake percentage for both adrenals ranged from 0.15% to 0.52% in 21 patients without evidence of adrenal disease, with a mean of 0.33% +/- 0.1%; also from 0.22% to 1.5% in 22 patients with Cushing's disease, with a mean uptake of 0.78% +/- 0.35%. The absorbed dose to the adrenals was estimated to be 25 rads/mCi for patients without evidence of adrenal disease, and 57 rads/mCi for patients with Cushing's disease. Both values are calculated for the respective mean uptake percentages by using MIRD formalism.

Simplifying the dosimetry of carbon-11-labeled radiopharmaceuticals.

UNLABELLED: A two time-point sacrifice method is proposed as an alternative to conventional multiple time-point sacrifice methods to determine the organ cumulated activity of 11C-labeled radiopharmaceuticals. METHODS: Rat biodistribution data for 10 11C-labeled radiopharmaceuticals were analyzed to determine organ cumulated activity. Data were obtained at four sacrifice intervals 2-5 min, 10-15 min, 30-45 min and 1-1.5 hr postinjection. The organ absorbed dose per unit administered radioactivity (mGy/MBq) was calculated using all four data points and combinations of limited data. The objective was to determine if a limited sampling technique would provide sufficient accuracy in estimating absorbed dose. RESULTS: Residence times calculated using two time-points acquired during the first half-life of 11C were either equivalent or positively biased compared to using all sacrifice times. Overall, 87% of the residence times assessed were conservative compared to the multipoint method. For bladder organs, a consistent negative bias was observed with the reduced sacrifice method. CONCLUSION: Analysis of animal biodistributions using a reduced sacrifice protocol provides results in good agreement with and generally conservative to results using all sacrifice intervals. Correction factors are required for the urinary bladder and gallbladder when using the simplified technique due to bias. The bladder was often the limiting organ in determining human administered activity.

Nonmyeloablative iodine-131 anti-B1 radioimmunotherapy as outpatient therapy.

UNLABELLED: The expected effective dose equivalent to an individual from contact with 131I anti-B1 radioimmunotherapy (RIT) patients released immediately after therapeutic infusion was estimated. METHODS: Effective dose equivalents were calculated retrospectively using data acquired on 46 patients treated with 1311 anti-B1 RIT as inpatients. Effective dose equivalents to members of the public were estimated using the method published in the Nuclear Regulatory Commission (NRC) Regulatory Guide 8.39, assuming the administered activity, the patient-specific effective half-life, the 0.25 occupancy factor, and no photon attenuation. Effective dose equivalents also were estimated using ionization chamber dose rates, measured immediately after therapeutic infusion and integrated to total decay based on the measured effective half-life. RESULTS: For the whole-body treatment absorbed dose limit of 75 cGy (75 rad), the administered 131I activity ranged from 2.1 to 6.5 GBq (56 to 175 mCi), and the measured dose rate at 1 m ranged from 70 to 190 microSv/hr (7 to 19 mrem/hr). The total-body effective half-life for these patients ranged from approximately 40 to 88 hr. Using the NRC method and not accounting for the attenuation of photons, the mean dose equivalent to the public exposed to an 131I anti-B1 patient discharged without hospitalization was 4.9 +/- 0.9 mSv (490 +/- 90 mrem). The range was 3.2-6.6 mSv (320 to 660 mrem), where 48% of patients would deliver a dose to another individual that is <5 mSv (500 mrem) (i.e., 48% of the patients would be allowed to return home immediately following the infusion). Using the measured dose rate method, the mean dose equivalent to an individual exposed to the same RIT patients was 2.9 +/- 0.4 mSv (290 +/- 40 mrem). The range was 2.0-3.7 mSv (200-370 mrem), where 100% of the estimated effective dose equivalents were <5 mSv (500 mrem). CONCLUSION: Based on calculated and patient-specific exposure data, outpatient RIT with nonmyeloablative doses of 131I should be feasible for all patients under current NRC regulations. Implementing outpatient RIT should make the therapy more widely available and more convenient and should lower patient care costs without exceeding accepted limits for public exposure to radiation.

Iodine-131 treatment of thyroid cancer: absorbed dose calculated from post-therapy scans.

The radiation absorbed dose for nine neck lesions distributed among four thyroid-cancer patients was measured directly from images taken after administration of a treatment dose of 131I. The tumor volume was measured with anterior plus lateral pinhole images by determining magnification and assuming an ellipsoidal shape. Uptake and effective half-life were determined from serial anterior images by use of a calibration curve. Dose lower limits ranged from 2,400 to 29,900 rad. Response to treatment was judged on the basis of one or more follow-up scans at least 8 mo later. All lesions responded to the therapy administration which ranged from 150 to 175 mCi.

Determination of iodine-131 diagnostic dose for imaging metastatic thyroid cancer.

The dose of radioiodine (131I) used to survey patients for metastatic functioning thyroid cancer varies from 0.2 mCi to 30.0 mCi. Higher doses have occasionally revealed more tumors, but deliver more radiation to the patient. We asked which dose would be sufficient to detect metastatic deposits. Using a water tank with small-source phantoms, we sought to determine: the minimum volume and concentration of activity capable of being imaged, effects of background and source depth on detectability, and a practical 131I tracer dose based on these findings. Two gamma cameras affixed with high-energy collimators of different design were used to evaluate the capabilities of two instrument systems. The lowest activity detectable at the water surface was 0.03 microCi, in volumes of 10 to 300 microliters. Background activity at 0.01 microCi/ml resulted in a three to tenfold loss of detectability; computer subtraction of background did not improve results. We assumed that the minimum beneficial treatment would be 4,500 rad, a dose delivered by 200 mCi of 131I to a tumor with 0.05% uptake of the dose per gram. From these assumptions, our data show that a 2 mCi diagnostic dose would detect 10 and 30 microliter lesions containing 0.05% or more of the dose per per gram, but only at the surface and in the absence of background radioactivity. Moreover, assuming patient motion and background activity, some potentially treatable lesions probably cannot be detected even with a 30 mCi diagnostic dose, using present-day equipment. Selection of a diagnostic dose should therefore acknowledge the limitations of scintigraphic detection and take into account the radiation burden incurred by studies repeated over years.

Phosphorus-32 therapy of cystic Grade IV astrocytomas: technique and preliminary application.

Instillation of [32P]chromic phosphate to cystic brain tumors was performed in six patients. Three patients had craniopharyngioma, two had Grade IV astrocytoma and one had Grade II astrocytoma. The cyst volumes ranged from 2 to 44 cc. A calculated dose of 20,000 rad was delivered to the cyst wall. The [32P]chromic phosphate dose given to achieve this dose ranged from 0.11 mCi to 2.5 mCi. Radionuclide leakage was not detected in either the central nervous system or the reticuloendothelial system by bremsstrahlung scanning. Stereotactic instillation was done in some cases, others had indwelling catheters. The frequency of cyst fluid aspiration in the three patients with craniopharyngioma decreased postinstillation. In the two patients with Grade IV astrocytoma, reductions in both the CT documented cyst size as well as the frequency of cyst aspiration were noted. We conclude that [32P]chromic phosphate installation by stereotactic or indwelling catheter method is a safe and helpful procedure in the management of cystic brain tumors.

In vivo imaging of the brain vesicular monoamine transporter.

UNLABELLED: In the search for an in vivo marker of monoamine nerve terminal integrity, we investigated methoxytetrabenazine (MTBZ) as a tracer of the brain synaptic vesicular monoamine transporter (VMAT2). METHODS: The biodistribution, metabolism and in vivo specificity of MTBZ binding were first evaluated in rodents and the human dosimetry was estimated. Subsequently, the human brain distribution of VMAT2 binding was determined in normal volunteers following administration of [11C]MTBZ. Brain regional time-activity curves were obtained, and parametric transport and binding images were calculated using arterial blood sampling and a two-compartment tracer kinetic model. RESULTS: Regional rat brain localization of [3H]MTBZ 15 min postinjection was consistent with the known monoamine nerve terminal density, which demonstrated the highest activity in the striatum, lateral septum, substantia nigra pars compacta, the raphe nuclei and the locus coeruleus. At this time, chromatography revealed over 82% of brain activity, but less than 47% of plasma activity corresponded to authentic MTBZ. In vivo [11C]MTBZ binding in the mouse brain was inhibited by coinjection of excess unlabeled dihydrotetrabenazine. In humans [11C]MTBZ had high initial brain uptake and rapid clearance from all regions, with longest retention in areas of high VMAT2 concentration. Parametric quantification of VMAT2 density revealed the highest distribution volume in the putamen and caudate with lower values in cerebral cortex and cerebellum. CONCLUSION: Carbon-11-MTBZ is a suitable ligand for PET quantification of the vesicular monoamine transporter in the human brain.

Radiopharmaceutical treatment of malignant pheochromocytoma.

Apart from relieving effects of secreted catecholamines, treatments of malignant pheochromocytoma have achieved little success. When the radiopharmaceutical, meta-[131I] iodobenzylguanidine (I-131 MIBG ), was found to concentrate in some malignant pheochromocytomas, we calculated that this agent could impart therapeutic doses of radiation to these tumors. We therefore treated five patients with two to four doses of I-131 MIBG prepared in high specific activity, 8-11 Ci/mmol. Individual doses were given at 3- to 10-mo intervals and in 97- to 197-mCi amounts. Two patients exhibited subjective and objective benefits. Their tumors declined in size (to 28% and 30% of original volumes) and in hormone secretion (to 50% or less of baseline rates). The other three patients manifested few symptoms before treatment and showed few or no objective improvement afterward. The tumors of the patients who responded to I-131 MIBG (a) appeared to be more rapidly growing, (b) received more cumulative rads, and (c) were more predominantly in soft tissues (in contrast to bone) than those in the patients who obtained little benefit. No toxic effects were encountered during the treatments, and only minor and temporary untoward responses were seen later.

Synthesis, rodent biodistribution, dosimetry, metabolism, and monkey images of carbon-11-labeled (+)-2 alpha-tropanyl benzilate: a central muscarinic receptor imaging agent.

Muscarinic cholinergic receptors (mAChR) are abundant in the brain, and the mAChR system mediates many aspects of brain function. There is evidence of alterations in muscarinic binding in degenerative brain disorders. A muscarinic receptor radioligand, carbon-11-(+)-2 alpha-tropanyl benzilate ([11C]TRB), has been prepared through N-[11C]methylation of N-desmethyl TRB, and evaluated in rodents and primates. Full body biodistribution in rats has been determined and the expected human dosimetry calculated. Comparisons with [11C]scopolamine in rats showed 2-6 times greater brain uptake of [11C] TRB. Highly specific and saturable binding of [11C]TRB in the striatum and cortex was demonstrated by greater than 85% blockade of uptake following QNB or scopolamine pretreatment. Striatum/cerebellum ratios in mice at 60 min exceeded 12.6. TLC analysis of rat tissues showed the absence of 11C-metabolites in brain and heart, and a rapid solid phase C-18 Sep-Pak method found that unmetabolized plasma [11C]TRB in monkeys fell from 81% at 5 min to 48% at 80 min. Finally, brains of living primates have been imaged using PET and [11C]TRB; regional localization was consistent with muscarinic receptor distribution. These results represent intermediate steps in the development of [11C]TRB for quantification of central muscarinic receptors in man.

In vivo mapping of cholinergic neurons in the human brain using SPECT and IBVM.

UNLABELLED: In the search for an in vivo marker of cholinergic neuronal integrity, we extended to human use the tracer (-)-5-[123I]iodobenzovesamicol (IBVM). METHODS: IBVM, an analog of vesamicol that binds to the acetylcholine transporter on presynaptic vesicles, was prepared with specific activity greater than 1.11 x 10(9) MBq mmole-1. After intravenous injection of [123I]IBVM, body distribution studies (n = 5) and brain SPECT studies (n = 5) were performed on normal human subjects (n = 10). SPECT images of the brain were collected sequentially over the first 4.5 hr following injection, and again 18 hr later. Data were realigned and transformed to stereotaxic coordinates, and localized activities were extracted for tracer kinetic analysis. The cerebral tracer input function was determined from metabolite-corrected radial arterial blood samples. The best data fit was obtained using a three-compartment model, including terms reflecting cerebral blood volume, exchange of free tracer between plasma and brain and specific binding. RESULTS: Dissociation of bound tracer was negligible for up to 4 hr. For the fitted parameters reflecting transport (K1) and binding site density index (k3), coefficients of variation were approximately 8% in cortical regions of interest. Relative distributions corresponded well with postmortem immunohistochemical values reported for the acetylcholine-synthesizing enzyme choline acetyltransferase, k3 (IBVM binding site density index), and tracer activity distribution at 22 hr, but not at 4 hr after injection. CONCLUSION: SPECT imaging of [123I]IBVM succeeds as an in vivo measure of cholinergic neuronal integrity and should be useful for the study of cerebral degenerative processes such as Alzheimer's disease.

Increased yield of human tissue-type plasminogen activator obtained by means of recombinant DNA technology.

Extra copies of the human tissue-type plasminogen activator (t-PA) gene were introduced into the Bowes melanoma cell line. We obtained a recombinant cell line (TRBM6) which secretes approximately ten-fold more t-PA than the parent cell line. The identity of the plasminogen activator made by the new cell line was confirmed by sizing on sodium dodecyl sulphate polyacrylamide gels and by specific quenching using anti-t-PA antibody. We estimate that the recombinant line produces t-PA at a rate of approximately 3 pg/cell/24 hr and that t-PA accumulates in the harvest medium at a rate of approximately 4000 International t-PA Units/ml/24 hr.

Technical considerations in in vivo thyroid studies.

Radionuclide thyroid studies, although among the oldest of clinical nuclear medicine procedures, continue to show growth and change. In the 7 years since thyroid studies were last reviewed in the Seminars, there have been marked changes in the preferred ways of doing these studies. In the areas of radiopharmaceuticals, 131I remains a useful agent in selected circumstances, but 99mTc-pertechnetate has become the agent of choice for imaging applications. Iodine-123 represents an exciting possibility for the future if problems in cost and radiopurity can be solved. New data on the dosimetry of the various agents allow for more rational choices among them, and useful guidelines can now be given for the use of these radiopharmaceuticals in problem areas such as pregnancy, nursing, and the pediatric age group. The scintillation camera with a pinhole collimator has become the instrument of choice for thyroid imaging, and the use of computers and the availability of systems for fluorescent scanning have added new possibilities for thyroid evaluation. Ancillary techniques such as ultrasound scanning also offer the possibility of improved diagnostic accuracy. These developments are reviewed in the context of clinical studies, together with a discussion of specific clinical applications and a brief look to the future.

In vivo biodistribution of 125IPIP and internal dosimetry of 123IPIP radioiodinated agents selective to the muscarinic acetylcholinergic receptor complex.

The development of new radioiodinated ligands for imaging the muscarinic acetylcholinergic complex (mAChR) using single photon emission computed tomography (SPECT) requires the evaluation of human organ doses prior to approval for human use. Animal biodistribution and excretion data were obtained and evaluated for IPIP, a new mAChR agent. Preliminary biodistribution studies were performed on four different stereoisomers of IPIP. A biokinetic model of the Z-(S)-IPIP stereoisomer was constructed for the rat and used to estimate the internal absorbed dose in humans based on an extrapolation of the rat model. The thyroid is the critical organ for this radiopharmaceutical, with an absorbed dose estimate of 2.4 mGy/MBq for both males and females, when labeled with 123I. Even when blocked, the thyroid is still the critical organ, yet with a 90% dose reduction. The heart and brain receive the next highest doses in both males and females. Effective dose estimates for the use of pure 123I-PIP in humans are 0.16 mSv/MBq for males and 0.14 mSv/MBq for females. The biodistribution studies of the Z-(S)-IPIP stereoisomer showed the most promise as a successful agent for imaging muscarinic receptor sites in the heart and brain. IPIP also demonstrated potential as a therapeutic radiopharmaceutical for some colon carcinomas where muscarinic receptor sites are expressed in the tumor cells. These results provide preliminary data for use of IPIP in clinical studies on humans.

Characterization of [11C]tetrabenazine as an in vivo radioligand for the vesicular monoamine transporter.

[11C]Tetrabenazine ([11C]TBZ) is a new in vivo radioligand for positron emission tomographic (PET) imaging of vesicular monoamine transporters. The in vivo distribution, metabolism and pharmacological specificity of [11C]TBZ has been determined in rodents. Regional mouse brain retention of [11C]TBZ is highest in brain regions with greatest monoaminergic innervation (striatum, hypothalamus) and can be reduced with ligands for the monoamine vesicular transporter (TBZ, ketanserin) but not haloperidol, a dopamine D2 receptor antagonist. Chromatographic analysis of rat blood demonstrated rapid metabolism of [11C]TBZ to radiolabeled metabolites (alpha- and beta -[11C]dihydrotetrabenazine) resulting from reduction of the 2-keto group. These metabolites, as well as a third potential metabolite, 9-O-desmethylTBZ, have been synthesized in unlabeled form and all three were shown to be capable of greatly reducing in vivo accumulation of [11C]TBZ in mouse striatum and hypothalamus. Whole body biodistribution of radioactivity after [11C]TBZ injection was determined in rats, and the data used to calculate the expected human dosimetry from this radiotracer. These studies demonstrated that [11C]TBZ can be safely administered for in vivo PET imaging and semi-quantitative determination of vesicular monoamine transporters in living human brain, but quantitative pharmacokinetic modeling of radioactivity distribution will be complicated by the presence of pharmacologically active metabolites.