Remco J.J. Knol

SPECT imaging of the dopaminergic system in (premotor) Parkinson's disease

In studies on (premotor) Parkinsons disease (PD), single photon emission computed tomography (SPECT) studies have focused on imaging of the presynaptic dopamine transporter (DAT) and postsynaptic dopamine D2 receptors (D2Rs). Here we review the results of SPECT studies on the dopaminergic system in PD, with particular emphasis on: the accuracy of SPECT imaging of the dopaminergic system to detect alternations of the dopaminergic system in early PD, the diagnostic accuracy of DAT SPECT in PD, the contribution of DAT imaging to detect preclinical phases of PD, and the potential role of SPECT imaging to monitoring progression of dopaminergic degeneration in PD.

[123I]FP-CIT binding in rat brain after acute and sub-chronic administration of dopaminergic medication

Abstract.The recently developed radioligand [123I]FP-CIT is suitable for clinical single-photon emission tomography (SPET) imaging of the dopamine (DA) transporter in vivo. To date it has remained unclear whether dopaminergic medication influences the striatal [123I]FP-CIT binding. The purpose of this study was to investigate the influence of this medication on [123I]FP-CIT binding in the brain. We used an animal model in which we administered dopaminomimetics, antipsychotics and an antidepressant. In vivo [123I]FP-CIT binding to the DA and serotonin transporters was evaluated after sub-chronic and acute administration of the drugs. The administered medication induced small changes in striatal [123I]FP-CIT binding which were not statistically significant. As expected, the DA reuptake blocker GBR 12,909 induced a significant decrease in [123I]FP-CIT binding. [123I]FP-CIT binding in the serotonin-rich hypothalamus was decreased only after acute administration of fluvoxamine. The results of this study suggest that dopaminergic medication will not affect the results of DA transporter SPET imaging with [123I]FP-CIT.

In vitro and ex vivo storage phosphor imaging of short-living radioisotopes.

Storage phosphor imaging may be of value for biodistribution studies of short-living radiotracers in small animals. Efficiency, sensitivity and resolution of imaging plates for short-living radioisotopes vary considerably but linear response to many radioisotopes was shown previously. However, these properties have not been compared directly for larger series of short-living radioisotopes, and only few studies have directly compared data obtained from phosphor images of tissue slices with results from dissection biodistribution studies. Therefore, we evaluated the properties of imaging plates for 11 short-living radioisotopes (18F, 32P, 67Ga, 89Sr, (99m)Tc, 90Y, 111In, 123I, 125I, 131I and 201Tl). We also evaluated the biodistribution of [123I]FP-CIT in rat brain using both the phosphor technique and conventional dissection methods. The imaging system showed a linear response for all tested radioisotopes over a wide range of radioactive concentrations and the efficiency, sensitivity and resolution varied greatly for the tested radioisotopes. Shielding experiments revealed the contribution of the various emission products of radioisotopes to these properties. However, quantitative biodistribution studies with radiotracers that are labeled with all tested radioisotopes, even 123I, are feasible. The results from the ex vivo biodistribution study, using [123I]FP-CIT as a radiotracer were similar for the phosphor imaging technique as compared to the dissection technique. Advantages of phosphor imaging in radiotracer distribution studies in rat brain as compared to dissection experiments may be more precise measurements, possibility to reanalyze imaging data and 3D-reconstruction. In conclusion, phosphor imaging is an attractive alternative for biodistribution studies of short-living radiotracers in small animals.

Design, Synthesis, Radiolabeling, and in Vitro and in Vivo Evaluation of Bridgehead Iodinated Analogues of N-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexa necarboxamide (WAY-100635) as Potential SPECT Ligands for the 5-HT(1A) Receptor

Here we describe the design, synthesis, and pharmacological profile of 5-HT(1A) receptor ligands related to 1 (WAY-100635). The cyclohexyl moiety in 1 and its O-desmethylated analogue 3 were replaced by the bridgehead iodinated bridge-fused rings: adamantyl, cubyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.1]heptyl. All analogues displayed a (sub)nanomolar affinity for the 5-HT(1A) receptor in vitro. Compounds 6b and 7b appeared to be selective for this receptor over other relevant receptors and could easily be iodinated with radioactive iodine-123. In humane hepatocytes, [(123)I]6b showed a low propensity for amide hydrolysis and a stable carbon-iodine bond. The biodistribution of [(123)I]6b and [(123)I]7b in rats revealed that the carbon-iodine bond was also stable in vivo. Unfortunately, the brain uptake and the specificity for both radioligands were significantly lower than those of the parent molecule 1. In conclusion, the designed tracers are not suitable for SPECT imaging.

In vivo [(123)I]CNS-1261 binding to D-serine-activated and MK801-blocked NMDA receptors: A storage phosphor imaging study in rats.

Disturbances of activity of the glutamatergic neurotransmitter system in the brain are present in many neuropsychiatric disorders. The N‐methyl‐D‐aspartate (NMDA) receptor is the most abundant receptor of the glutamatergic system. In the neurodegenerative events of Alzheimers disease, excessive activation of NMDA receptors may contribute to neuronal death. Inhibition of NMDA receptor activation may have neuroprotective effects and (semi)quantitative imaging of the activated system may help in the selection of patients for such inhibition therapies. In this study we evaluated [123I]CNS‐1261 binding in the rat brain. This radiotracer binds in vivo to the MK801 binding site of activated NMDA receptors. To determine the optimal time point for ex vivo assessments after bolus injection [123I]CNS‐1261 binding in rats, we performed a time course biodistribution study using dissection techniques. [123I]CNS‐1261 binding was also studied in the rat brain using autoradiography by means of storage phosphor imaging, with prior facilitation of NMDA receptor activation by injection of the potent coagonist D‐serine and after blocking of the NMDA receptor binding site by MK801 injection in D‐serine pretreated rats. Measurements of [123I]CNS‐1261 uptake matched the distribution of similar tracers for the MK801 binding site of the NMDA receptor and revealed an optimal time point of 2 h post injection for the assessment of tracer distribution in the rat brain. The blocking experiments indicated specific binding of [123I]CNS‐1261 to NMDA receptors but also a considerable amount of nonspecific binding. Facilitation of NMDA receptor activation by D‐serine did not result in an enhancement of binding of the radiotracer in the NMDA receptor‐rich rat hippocampus compared to the untreated group, as measured by autoradiography. In conclusion, our study has shown that [123I]CNS‐1261 binding is influenced by NMDA receptor availability. However, high nonspecific binding limits quantification and small changes in receptor availability are unlikely to be detected. Synapse 63:557–564, 2009.

Iodine-123 labelled nor-β-CIT binds to the serotonin transporter in vivo as assessed by biodistribution studies in rats

Abstract. Iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)nortropane (nor-β-CIT), a radioiodinated cocaine analogue, was evaluated as an agent for the in vivo labelling of serotonin transporters by biodistribution studies in rats. Intravenous injection of [123I]nor-β-CIT resulted in high accumulation of radioactivity in brain areas with high densities of serotonin (hypothalamus) and dopamine transporters (striatum), although the binding was less pronounced in the hypothalamus. While binding of [123I]nor-β-CIT in the hypothalamus was blocked significantly by fluvoxamine (a selective serotonin transporter blocker) but not by GBR12,909 (a selective dopamine transporter blocker), the opposite was observed in the striatum. The results of this study indicate that [123I]nor-β-CIT, although not being a selective radioligand, binds specifically to serotonin transporters in the hypothalamus in vivo and thus suggest that [123I]nor-β-CIT promises to be a suitable radioligand for single-photon emission tomography imaging of serotonin transporters in humans.

Tako-tsubo cardiomyopathy: how to understand possible pathophysiological mechanism and the role of (123)I-MIBG imaging.

Tako-tsubo cardiomyopathy (TCM) is an increasingly recognized clinical syndrome characterized by acute reversible apical ventricular dysfunction, commonly preceded by exposure to severe physical or emotional stress. In this review, we give a short overview on clinical presentation and treatment of TCM and discuss the possible pathophysiological mechanisms of TCM and the role of various non-invasive imaging modalities in TCM with a focus on the potential role of 123I-meta-iodobenzylguanidine (MIBG) scintigraphy. Currently, the dominating hypothesis on the pathophysiology of TCM postulates that high levels of the neurotransmitter epinephrine may trigger a change in intracellular signaling in ventricular myocytes. More specific, epinephrine stimulates G-protein coupled β2 adenoreceptors (β2AR) which are located on ventricular myocytes. Normal levels of this neurotransmitter predominantly stimulate the intracellular G-protein, and induce a positive inotropic effect. However, with significant increasing levels of epinephrine, the predominance of stimulation is shifted from G-stimulating to the G-inhibitor protein coupling, which leads to a negative inotropic effect. Interestingly, this negative inotropic effect is the largest in the apical myocardium where the β2AR:β1AR ratio is the highest within the heart. Echocardiography and ventriculography are essential to diagnose TCM, but new imaging tools are promising to diagnose TCM and to evaluate therapeutic efficacy. Cardiovascular magnetic resonance can be used to differentiate TCM from other myocardial diseases, such as myocarditis. 123I-meta-iodobenzylguanidine (123I-MIBG) scintigraphy can be used to assess ventricular adrenergic activity and may guide optimization of individual (pharmacological) therapy. These new insights into the possible pathophysiological mechanisms and novel diagnostic imaging modalities can be used as starting point for the development of international guidelines of TCM which may increase the awareness, and optimize the treatment of TCM.

Synthesis and evaluation of iodinated TZTP-derivatives as potential radioligands for imaging of muscarinic M2 receptors with SPET

A series of iodinated thiadiazolyltetrahydro-1-methyl-pyridine (TZTP) compounds was synthesized and evaluated in vitro and in vivo as potential radioligands for imaging of the muscarinic M2 receptor subtype with SPET. One of these compounds, 5-(E)-iodopentenylthio-TZTP, has high in vitro affinity (Ki = 4.9 nM) and moderate selectivity for the muscarinic M2 receptor subtype. Although the uptake pattern in the biodistribution studies in rats is consistent with muscarinic M2 receptor disribution, specific in vivo binding to these receptors could not be demonstrated. The usefulness of this tracer in human SPET imaging may therefore be limited.

Decreased ipsilateral [123I]iododexetimide binding to cortical muscarinic receptors in unilaterally 6-hydroxydopamine lesioned rats

INTRODUCTION Dysfunction of the cholinergic neurotransmitter system is present in Parkinsons disease, Parkinsons disease related dementia and dementia with Lewy bodies, and is thought to contribute to cognitive deficits in these patients. In vivo imaging of the cholinergic system in these diseases may be of value to monitor central cholinergic disturbances and to select cases in which treatment with cholinesterase inhibitors could be beneficial. The muscarinic receptor tracer [(123)I]iododexetimide, predominantly reflecting M1 receptor binding, may be an appropriate tool for imaging of the cholinergic system by means of SPECT. In this study, we used [(123)I]iododexetimide to study the effects of a 6-hydroxydopamine lesion (an animal model of Parkinsons disease) on the muscarinic receptor availability in the rat brain. METHODS Rats (n=5) were injected in vivo at 10-13 days after a confirmed unilateral 6-hydroxydopamine lesion. Muscarinic receptor availability was measured bilaterally in multiple brain areas on storage phosphor images by region of interest analysis. RESULTS Autoradiography revealed a consistent and statistically significant lower [(123)I]iododexetimide binding in all examined neocortical areas on the ipsilateral side of the lesion as compared to the contralateral side. In hippocampal and subcortical areas, such asymmetry was not detected. CONCLUSIONS This study suggests that evaluation of muscarinic receptor availability in dopamine depleted brains using [(123)I]iododexetimide is feasible. We conclude that 6-hydroxydopamine lesions induce a decrease of neocortical muscarinic receptor availability. We hypothesize that this arises from down regulation of muscarinic postsynaptic M1 receptors due to hyperactivation of the cortical cholinergic system in response to dopamine depletion. ADVANCES IN KNOWLEDGE In rats, dopamine depletion provokes a decrease in neocortical muscarinic receptor availability, which is evaluable by [(123)I]iododexetimide imaging. IMPLICATIONS FOR PATIENT CARE This study may further underline the role of a dysregulated muscarinic system in patients with Lewy body disorders.

PET and SPECT Imaging of the Central Dopamine System in Humans

The neurotransmitter dopamine plays a role in many different functions of the human brain, ranging from psychomotor planning to cognition. This short review addresses which parts of the dopamine system can be imaged quantitatively in the living human brain using positron-emission tomography (PET) or single-photon emission computed tomography (SPECT).