Bioconjugate Chem. 2005, 16, 27−31
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ARTICLES Positron-Labeled Dopamine Agonists for Probing the High Affinity States of Dopamine Subtype 2 Receptors Dah-Ren Hwang,* Raj Narendran, and Marc Laruelle Department of Psychiatry, Columbia University, 1051 Riverside Drive, Unit 31, New York, New York 10032 . Received July 12, 2004; Revised Manuscript Received October 14, 2004
It is well documented that guanidine nucleotide-coupled dopamine subtype 2 receptors (D2) are configured in high and low affinity states for the dopamine agonist in vitro. However, it is still unclear whether these functional states exist in vivo. We hypothesized that positron-labeled D2 agonist and Positron Emission Tomography can be used to probe these functional states noninvasively. Recently, we demonstrated in nonhuman primates that N-[11C]propyl-norapomorphine (NPA), a full D2 agonist, is a suitable tracer for imaging the high affinity states of D2 receptors in vivo. We also developed kinetic modeling method to derive receptor parameters, such as binding potential (BP) and specific uptake ratios (V3′′). When coupled with a dopamine releasing drug, amphetamine, NPA was found to be more sensitive than antagonist tracers, such as [11C]raclopride (RAC), to endogenous dopamine concentration changes (by about 42%). This finding suggests that NPA is a superior tracer for reporting endogenous DA concentration. In addition, the difference of the BP or V3′′ of NPA and RAC under control and amphetamine challenge conditions could be used to estimate the functional states of D2 receptors in vivo. On the basis of our findings and the assumptions that NPA binds only to the high affinity states and RAC binds equally to both affinity states, we proposed that about 70% of the D2 receptors are configured in the high affinity states in vivo.
INTRODUCTION
The hyperdopaminergic hypothesis of schizophrenia is well supported by compelling evidence such as that all antipsychotics are potent dopamine D2 receptor antagonists and that hyperdopaminergic activities of schizophrenic patients are detectable by neuroimaging techniques. However, the functional states of the D2 receptors in this disease are still unknown. Like other guanine nucleotide protein (G-protein)coupled receptors, D2 receptors are configured into Gprotein-coupled (GR) and -uncoupled (R) states, as proposed in the ternary complex model (1, 2). In this model, dopamine (DA) or other D2 agonists bind with high affinity to GR (D2 high) and low affinity to the low affinity states (D2 low). However, a D2 antagonist will bind with equal potency to the high and the low affinity states. Therefore, an agonist tracer is needed to probe the D2 high receptors in vivo. In addition, since DA binds with high affinity to the D2 high, an agonist tracer will be more sensitive to endogenous DA concentration changes, and hence it will be a superior tracer for reporting endogenous DA concentrations. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) have been used successfully to study the competition between endogenous DA and radiotracers (3). These neuroimaging techniques involved a baseline scan followed by a drug challenge scan. The baseline uptake of the tracer (such as [123I]IBZM or RAC) is first determined. Then, a DA enhancing drug, such as amphetamie (AMPH), is given. The drug leads * To whom correspondence should be addressed. Tel: (212) 543 5901; Fax: (212) 568 6171; e-mail:
[email protected].
to massive increases of DA in the synapse that compete with tracer binding and result in the decrease of tracer uptake. The difference of tracer bindings between these two scans becomes an index of synaptic dopamine concentrations. The endogenous concentrations of DA at baseline and after AMPH challenge can be measured using microdialysis technique. A linear relationship exists between the changes of tracer binding (detected by IBZM SPECT or RAC PET scans) and the DA concentration (measured by microdialysis) (Figure 1) (4, 5). With increasing doses of AMPH (0.3, 0.5, and 1 mg/kg), a 7-, 10-, and 15-fold increase in endogenous DA concentration and 20%, 30%, and 40% decrease of tracer bindings, respectively, were observed. The linear relationship of the AMPH dose response curve demonstrated that the decrease of tracer uptake is an index of endogenous DA concentration. It also revealed that a 40% increase in DA concentration only resulted in 1% decrease of [123I]IBZM, and a 44% increase in DA concentration resulted in 1% decrease of RAC binding. The low sensitivity of antagonist to dopamine competition is observed. Examining the RAC PET images in Figure 1, one can easily appreciate the small 10% difference between the control (top image) and the AMPH (0.3 mg/kg, bottom). Importantly, the AMPH challenge image paradigm has revealed that the decrease in tracer binding under the AMPH condition is more in the schizophrenic patients (-15%) than in the normal controls (-9%). This observation offered a direct evidence of hyperdopaminergic activity in schizophrenia. The role of noninvasive brain imaging technique in understanding the pathophysiology of schizophrenia has recently been reviewed (6).
10.1021/bc049834n CCC: $30.25 © 2005 American Chemical Society Published on Web 12/29/2004
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Figure 1. Microdialysis and neuroimaging measurements of amphtamine-induced DA release. The graph on the left showed the linear relationship between the percent of displacement of [123I]IBZM binding (X-axis) and the peak dopamine concentration measured by microdialysis. The PET images on the right were obtained in healthy controls using [11C]raclopride. The top panel is the images under control conditions and the bottom panel is the image after a dose of amphetamine (0.3 mg/kg).
Figure 3. Positron-labeled apomorphine derivatives. Figure 2. Positron-labeled aminotetralin derivatives.
Unfortunately, this image paradigm revealed a ceiling effect of 40% decrease of tracer binding by DA enhancing drugs (3). This is based on the results from eight nonhuman primates (five with RAC and three with IBZM) and 11 human studies (six RAC and five IBZM). In these studies, the decrease of tracer binding potential (which is the ratio of striatal uptake to tracers activity in the blood) ranged from 10% to 40% with doses of AMPH ranged from 0.2 to 1 mg for nonhuman primates and 0.2-0.5 mg for humans. One possible explanation of the ceiling effect is that antagonist tracers (such as IBZM and RAC) bind with equal affinity to both high and low affinity states. However, only the bindings to the high affinity states are vulnerable to endogenous DA challenge. The 40% ceiling effect suggested that 40% of the D2 receptors are configured in the high affinity state. However, the best way to confirm the high and low affinity function states of D2 receptors is to use agonist tracer. Because DA agonist binds with high affinity to the high affinity states, it is expected that an agonist tracer will be more sensitive to endogenous DA concentration changes than that of an antagonist tracer. Therefore, an agonist tracer will be a superior probe for reporting endogenous DA concentration. Since the early 1990s, two classes of D2 agonists, apomorphine and aminotralin derivatives, have been evaluated as potential agonist PET tracers (Figures 2 and 3). In the aminotralin series, both 5- and 7-hydroxy-
aminotetralin derivatives have been prepared and evaluated. In 1993, Zijlstra et al. reported two fluoropropyl derivatives of 5-hydroxy-2-aminotetralin, compounds 1 and 2 in Figure 2 (7). However, both tracers showed no selective bindings in vivo. In 1994, Halldin et al. evaluated [11C]-7-hydroxy-2-N,N-dipropylaminotetralin (7-OHDPAT, 7, prepared by N-alkylation with [11C]propyl iodide) as a potential ligand for D3 receptor, and a striatum (target tissue) to cerebellum (reference tissue) ratio of 2.2 in monkey brain was reported (8). However, since the initial report, no detailed studies of 7-OH-DPAT were reported. Similarly, Brown et al. reported the preparation of [11C]PHNO, 8, via the formation of [11C]propionic amide followed by reduction, but in vivo evaluation of the tracer was never reported (9). More recently, Shi et al. reported that several 5-hydroxy-2-aminotetralin derivatives (both C-11 and F-18 labeled tracers, compounds 3 to 6 in Figure 2) have high affinity for the D2 receptors (10-13). The agonist properties of these tracers were demonstrated by in vitro autoradiography using rat brain slices. When tissues were incubated in the presence of nonhydrolyzable guanine nucleotide, GppNHp, which converts the high to the low affinity states, tracer uptakes are completely blocked. Monkey PET studies of tracers 3 to 6 revealed a striatum/ cerebellum ratios of about 2. Detailed evaluation of these tracers (particularly the optically active tracers) has not been reported. For the apomorphine series (Figure 3), Zijlstra et al. evaluated both [11C]apomorphine, 9, and [18F]fluoropropylnorapomorphine, 10, in rodents (14, 15). [11C]Apo-
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morphine had a striatum/cerebellum ratio of about 1.5, but the fluoro derivative did not show any specific uptake. Because of the low selective uptake, these tracers were not further evaluated. Halldin et al. reported two [11C]labeled N-propyl-nor-apomorphine (NPA) derivatives, 2-hydoxy-[11C-propyl]NPA, 11, and 2-O-[11C]methoxyNPA, 12. Initial primate studies showed that comppound 11 (prepared by reacting the norpropyl precursor with [11C]propyl iodide) had low brain uptake (16). On the other hand, 2-[11C]methoxy-NPA, prepared by reacting 2-hydroxy-NPA with [11C]methyl iodide, showed a moderate striatum/cerebellum ratio of 2 in monkey. Unfortunately, this tracer was not further characterized. Interestingly, one of the best characterized D2 agonist, N-propyl-norapomorphine (NPA), has not been the focus of PET tracer development. NPA is a full D2 agonist with Ki values of 0.4 nM and 23 nM for the D2 high and D2 low, respectively (17, 18). It also has high affinity for another D2 family receptors, the D3 subtype (Ki ) 0.3 nM). It has good D2 selectivity over other receptors (Ki for D1, 340 nM; R2, 480 nM; all other receptors, >1 µM). More importantly it has been used in humans for treating Parkinson’s disease. In addition, norapomorphine, the starting material for the radiolabeling of NPA, is commercially available. This greatly facilitated our preparation and evaluation of [11C]-labeled NPA. This article will focus on the use of [11C]-labeled NPA for in vivo imaging of the high affinity states of D2 receptors. The sensitivities of an agonist verse an antagonist PET tracer to endogenous dopamine concentration changes will be presented. EXPERIMENTAL PROCEDURES
Radiochemistry. [11C]NPA was prepared according to our published procedure (19). Briefly, a two-step labeling procedure, N-propionylation of norapomorphine followed by LAH reduction, was used for the preparation of [11C]NPA (19). This procedure yielded high specific activity (>1.5 mCi/nmol) and radiochemical purity (>95%) of NPA. [11C]Raclopride was prepared from desmethyl raclopride and [11C]methyl triflate with similar specific activity and radiochemical purity. Baboon PET Imaging. Detailed procedures can be found in two published articles (20, 21). Briefly, the baboon was anesthetized with isoflurane and body temperature maintained by a water blanket. After tracer injection, 120-min dynamic PET scans were started. For amphetamine challenge studies, amphetamine was given 5 min prior to tracer injection. Arterial blood samples were taken at different interval to get input function and to do metabolite analysis. Plasma free fraction was measured using ultrafiltration technique. PET Image Analysis. Detailed description can be found in our published article (21). Briefly, the outcome measures are the tissue distribution volume (VT), binding potentials (BP), and selective uptake ratios (V3′′). These terms are defined as follows:
VT ) Ctissue/Cblood
(1)
BPtissue ) VT tissue - VT reference region ) bound/free ) f1Bmax/KD (2) V3′′ ) BPtissue/VT reference region
(3)
where Ctissue is the radioactivity in the tissue detected by PET scan, Cblood is the amount of the parent tracer in the plasma (determined by measuring the radioactivity
Table 1. Reproducibility of ∆V3′′ and ∆BP Following Amphetamine (0.5 mg/kg) in the Same Baboon tracer
condition
∆V3′′, %
∆BP, %
[11C]raclopride
test retest test retest
-26 -25 -48 -46
-26 -21 -41 -52
[11C]NPA
in the plasma at different time point and corrected for the metabolites), Bmax is the total receptor density, KD is the tracer’s affinity for D2 receptors, and f1 is the plasma free fraction of the tracer. The effect of AMPH on tissue’s selective uptake is calculated as the difference of the BP or V3′′ of the preand post-AMPH scans divided by the BP or V3′′ of the pre-AMPH scan as defined in eqs 4 and 5:
∆BP ) (BPpre - BPpost)/BPpre
(4)
∆V3′′ ) (V3′′pre - V3′′post)/V3′′pre
(5)
RESULTS AND DISCUSSION
For the radiosynthesis of NPA, a two-step labeling procedure, N-propionylation of norapomorphine followed by LAH reduction, was developed (19). This procedure yielded high SA (>1.5 mCi/nmol) and radiochemical purity (>95%) of NPA. Biodistribution in rats showed a striatum/cerebellum ratio of 4.4 at 60 min post tracer injection. Baboon PET scans showed moderate striatal uptakes and the striatum/cerebellum ratio reached 2.8 at 45 min post tracer injection, which is higher than any D2 agonist PET tracer reported to date. More importantly, the uptake was blocked by haldol at an iv dose of 0.2 mg/kg. These results strongly suggest that NPA is a selective D2 receptor PET ligand. Recently, we demonstrated that a one-tissue-compartment kinetic modeling method with metabolite corrected arterial input function is suitable for deriving receptor parameters, such as the tissue distribution volume (VT), binding potentials (BP) and selective uptake ratios (V3′′) (20). Table 1 shows the ∆V3′′ of RAC and NPA in the same baboon using a dose of 0.5 mg/kg AMPH. A decrease of 26% and 48% was observed for RAC and NPA, respectively (21). The reliability of this outcome measure under test and retest conditions is excellent. The ∆V3′′ value is more consistent than the ∆BP value. The voxelwise V3′′ maps of RAC and NPA under control and AMPH conditions in the same baboon are shown in Figure 4. The large effect of amphetamine on NPA V3′′ is evident. More detailed studies were then conducted in three additional baboons (21). Each baboon received both RAC and NPA and studied under control and AMPH treated conditions (3 doses: 0.3, 0.5, and 1 mg/kg). A total of 36 scans were performed. For these scans, there were no significant difference in injected dose, mass (both control and AMPH conditions), free fractions, clearance rate, and the reference tissue distribution volume (VT CER). However, the VT CER did drop under AMPH conditions, which only results in underestimates of the true effect. The AMPH dose effects on the ∆V3′′ of RAC and NPA are shown in Figure 5. Under all doses examined, NPA consistently shows higher decreases of selective uptakes and the difference are significant in all doses examined. If we compare the AMPH effect on NPA (triangle) and antagonist tracers (RAC circle and IBZM square), one can clearly see that a ceiling effect (60%) is observed with NPA (Figure 6). Assuming that NPA binds only to the
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Figure 4. Voxelwise V3′′ maps of [11C]NPA and [11C]raclopride in the same baboon under control and post amphetamine (0.5 mg/ kg) challenge conditions. The left panel is the [11C]NPA V3′′ maps under baseline (left) and post amphetamine challenge (right). The middle panel is the MRI images of the baboon brain correspond to those of the PET images. The right panel is the [11C]raclopride V3′′ maps under baseline (left) and post amphetamine challenge (right). In this paired study the displacement (∆V3′′) for [11C] NPA and [11C]raclopride are - 48% and - 26%, respectively.
Figure 5. Effect of amphetamine on V3′′ of [11C]NPA (solid triangle), [11C]raclopride (solid circle), and [123I]IBZM (solid square). The X-axis is the dose of amphetamine (mg/kg), and the Y-axis is the percent change of V3′′ (∆V3′′). The figure illustrates that the effect of amphetamine on agonist tracer ([11C]NPA, Khigh ) 0.2 nM) is larger than antagonist tracers ([11C]raclopride, KD ) 1.2 nM; and [123I]IBZM, KD ) 0.4 nM). Its effect on antagonists is similar. These results imply that the agonist tracer is more sensitive to endogenous dopamine concentration changes than antagonist tracer.
D2 high, the percent of high affinity states (ratio of Rhigh to Bmax) can be calculated from the ratios of ∆BPRAC and ∆BPNPA according to the following equation:
Rhigh/Bmax ) [∆BPRAC/∆BPNPA] (1 - R) + R
(6)
where R is the percent of receptor occupied by DA. Detailed derivation of the equations can be found in our recent paper (21). Since only 60% of the NPA binding (D2 high) was displaceable by endogenous DA, this portion of D2 high is defined as RHS (synaptic high affinity states) and the rest of D2 high as RHNS (nonsynaptic high affinity states). This means that RHS equals 60% of D2 high that are not occupied by DA. Our results showed a ∆BPRAC/∆BPNPA ratio of 0.7 (21). If we assume R equals 10% (i.e. 10% of the D2 high is already occupied by DA), a Rhigh /Bmax ratio of 0.73 was obtained from eq 6. It suggested that 73% of the D2 receptors are configured in the high affinity state (i.e. D2 high/Bmax ) 73%). Since we assume that 10% of the D2 high are occupied by DA and we observed a maximum of 60% of NPA binding that can be displaced by endogenous DA, the percent of RHS and RHNS are calculated to be 38% (i.e. 0.6 × (0.73 - 0.1)) and 25%, respectively.
Figure 6. Revised model of D2 receptors. The extended model (panel B) is derived from our present result. The new model divides the receptors into D2 high and D2 low. An 10% of the D2 high are assumed to be occupied by dopamine at baseline. Our result suggests that 40% of D2 high are protected from dopamine challenge. Therefore, the D2 high was further divided into synaptic and nonsynaptic compartments. Since we observed a 70% difference between the effect of amphetamine on [11C]NPA and [11C]raclopride, this suggests that 73% of the receptors are the D2 high. Thus we calculated the following proportion of receptors for the extended model: 10% occupied by dopamine at baseline, 38% of the Rhigh are vulnerable to dopamine challenge (synaptic D2 high), 25% of the Rhigh are protected from dopamine occupancy (nonsynaptic D2 high), and 27% are Rlow.
On the basis of these results, we modified the original D2 model, which suggests that only 50% of the D2 receptors are configured in high affinity states, to the new model that 73% of the D2 receptors are configured in the high affinity states (D2 high). We also proposed that, among the 73% of D2 high, 10% is already occupied by DA at baseline, 38% is the synaptic high affinity state that is vulnerable to AMPH challenge, and 25% is the nonsynaptic high affinity state that is not vulnerable to challenge. Recently, we performed in vivo saturation binding studies in baboon with both NPA and RAC (unpublished results). From these experiments we obtained the in vivo KD of 1.44 nM for RAC and 0.15 nM for NPA. The Bmax obtained with RAC and NPA are 26 and 20 nM, respec-
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tively. From these numbers, the percent of D2 high is calculated to be 79%, which is remarkably close to the number we derived from the combined RAC and NPA studies. In conclusion, we found that in vivo binding of NPA is more vulnerable to competition by endogenous DA than that of RAC (by 42%). NPA appears to be a superior probe to report on endogenous DA fluctuations. We also found that about 60% of the NPA bindings are vulnerable to endogenous competition (versus 44% for RAC), which agrees with previous findings in mice using [3H]NPA (22). Assuming that, at tracer dose, NPA binds only to D2 high, our results implied that about 70% of D2 receptors are D2 high. Recent saturation studies confirmed that NPA Bmax () Rhigh) is 70% of RAC Bmax. There is no doubt that neuroimaging techniques such as PET and SPECT are powerful tools to explore biochemistry in vivo. This technique depends on the successful development of appropriate tracers. It is obvious that chemists play a vital role in this field. Equally important is to establish collaborations among different disciplines that widen the scope of the application. ACKNOWLEDGMENT
This research was supported by a grant from NIMH (RO1 62089-01) and a Young Investor Award form NARSAD. We thank the technical supports of the members of the Division of Functional Brain Mapping. LITERATURE CITED (1) De Lean, A., Stadel, J., and Lefkowitz, R. (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptors. J. Biol. Chem. 255, 7108-7117. (2) Samama, P., Cotecchia, S., Costa, T., and Lefkowitz, R. (1993) A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ernary complex model. J. Biol. Chem. 268, 4625-4636. (3) Laruelle, M. (2000) Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J. Cereb. Blood Flow Metab. 20, 423-451. (4) Laruelle, M., Iyer, R., Al-Tikriti, M., Zea-Ponce, Y., Malison, R., Zoghbi, S., Baldwin, R., Kung, H., Charney, D., Hoffer, P., Innis, R., and Bradberry, C. (1997) Microdialysis and SPECT measurements of amphetamine-induced dopamine release in nonhuman primates. Synapse 25, 1-14. (5) Endres, C., Kolachana, B., Saunders, R., Su, T., Weinberger, D., Breier, A., Eckelman, W., and Carson, R. (1997) Kinetic modeling of [11C]raclopride: combined PET-microdialysis studies. J. Cereb. Blood Flow Metab. 17, 932-942. (6) Laruelle, M. (2000) The role of endogenous sensitization in the pathophysiology of schizophrenia: Implications from recent brain imaging studies. Brain Res. Rev. 31, 371-384. (7) Zijlstra, S., Elsinga, P., Oosteruis, E., Visser, G., Korf, J., and Vaalburg, W. (1993) Synthesis and in vivo distribution in the rat of several fluorine-18 labeled 5-hydroxy-2-aminoetraline derivatives. Appl. Radiat. Isot. 44, 473-480. (8) Halldin, C., Swahn, C., Suhara, L., Farde, L., Karlsson, P., Sokoloff, P., and Sedvall, G. (1994) Preparation of (+)-[propyl11C]7-OH-DPAT, a selecive dopamine D3 receptor agonist for PET. J. Labelled Compd. Radiopharm. 35, 471-472. (9) Brown, D., Luthra, S., Brad, F., Prenant, C., Dijkstra, D., Wikstrom, H., and Brooks, D. (1997) Labeling of the D2 agonist using [11C]-propionyl chloride. J. Labelled Compd. Radiopharm. 40, S565.
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BC049834N
