Receptor Imaging Research Articles

Design of iodinated radioligands for SPECT imaging of central human 5-HT4R using a ligand lipophilicity efficiency approach.

A series of iodinated ligands for the SPECT imaging of 5-HT4 receptors was designed starting from the previously reported hit MR-26132. We focused on the modulation of the piperidine-containing lateral chain by introducing hydrophilic groups in order to decrease the liphophilicity of the new ligands. All the synthesized compounds were tested for their binding affinities on 5-HT4Rs and based on the Ligand Lipophilicity Efficiency approach, compound 13 was further selected for radioiodination with iodine-125 and imaging experiments. Compound 13 showed its ability to displace the specific signal of the reference compound [125I]SB-207710 but no significant detection of [125I]13 was observed in vivo in SPECT experiments.

Radiosynthesis and preclinical evaluation of [11 C]Cimbi-701 - Towards the imaging of cerebral 5-HT7 receptors.

The serotonin 7 (5-HT7 ) receptor is suggested to be involved in a broad variety of CNS disorders, but very few in vivo tools exist to study this important target. Molecular imaging with positron emission tomography (PET) would enable an in vivo characterization of the 5-HT7 receptor. However, no clinical PET radiotracer exists for this receptor, and thus we aimed to develop such a tracer. In this study, we present the preclinical evaluation of [11 C]Cimbi-701. Cimbi-701 was synthesized in a one-step procedure starting from SB-269970. Its selectivity profile was determined using an academic screening platform (NIMH Psychoactive Drug Screening Program). Successful radiolabeling of [11 C]Cimbi-701 and subsequent in vivo evaluation was conducted in rats, pigs and baboon. In vivo specificity was investigated by 5-HT7 and σ receptor blocking studies. P-gp efflux transporter dependency was investigated using elacridar. [11 C]Cimbi-701 could successfully be synthesized. Selectivity profiling revealed high affinity for the 5-HT7 (Ki = 18 nM), σ-1 (Ki = 9.2 nM) and σ-2 (Ki = 1.6 nM) receptors. In rats, [11 C]Cimbi-701 acted as a strong P-gp substrate. After P-gp inhibition, rat brain uptake could specifically be blocked by 5-HT7 and σ receptor ligands. In pig, high brain uptake and specific 5-HT7 and σ-receptor binding was found for [11 C]Cimbi-701 without P-gp inhibition. Finally, low brain uptake was found in baboons. Both the specific σ-receptor binding and the low brain uptake of [11 C]Cimbi-701 displayed in baboon discouraged further translation to humans. Instead, we suggest exploration of this structural class as results indicate that selective 5-HT7 receptor imaging might be possible when more selective non-P-gp substrates are identified.

Synthesis and preliminary studies of 11C-labeled tetrahydro-1,7-naphthyridine-2-carboxamides for PET imaging of metabotropic glutamate receptor 2.

Selective modulation of metabotropic glutamate receptor 2 (mGlu2) represents a novel therapeutic approach for treating brain disorders, including schizophrenia, depression, Parkinson's disease (PD), Alzheimer's disease (AD), drug abuse and addiction. Imaging mGlu2 using positron emission tomography (PET) would allow for in vivo quantification under physiological and pathological conditions and facilitate drug discovery by enabling target engagement studies. In this paper, we aimed to develop a novel specific radioligand derived from negative allosteric modulators (NAMs) for PET imaging of mGlu2.Methods. A focused small molecule library of mGlu2 NAMs with tetrahydro naphthyridine scaffold was synthesized for pharmacology and physicochemical evaluation. GIRK dose-response assays and CNS panel binding selectivity assays were performed to study the affinity and selectivity of mGlu2 NAMs, among which compounds 14a and 14b were selected as PET ligand candidates. Autoradiography in SD rat brain sections was used to confirm the in vitro binding specificity and selectivity of [11C]14a and [11C]14b towards mGlu2. In vivo binding specificity was then studied by PET imaging. Whole body biodistribution study and radiometabolite analysis were conducted to demonstrate the pharmacokinetic properties of [11C]14b as most promising PET mGlu2 PET ligand.Results. mGlu2 NAMs 14a-14g were synthesized in 14%-20% yields in five steps. NAMs 14a and 14b were selected to be the most promising ligands due to their high affinity in GIRK dose-response assays. [11C]14a and [11C]14b displayed similar heterogeneous distribution by autoradiography, consistent with mGlu2 expression in the brain. While PET imaging study showed good brain permeability for both tracers, compound [11C]14b demonstrated superior binding specificity compared to [11C]14a. Further radiometabolite analysis of [11C]14b showed excellent stability in the brain.Conclusions. Compound 14b exhibited high affinity and excellent subtype selectivity, which was then evaluated by in vitro autoradiography and in vivo PET imaging study after labeling with carbon-11. Ligand [11C]14b, which we named [11C]MG2-1904, demonstrated high brain uptake and excellent in vitro/in vivo specific binding towards mGlu2 with high metabolic stability in the brain. As proof-of-concept, our preliminary work demonstrated a successful example of visualizing mGlu2 in vivo derived from NAMs, which represents a promising chemotype for further development and optimization aimed for clinical translation.

Fluorinated and [18F]fluorinated morphinan based opioid ligands.

It is well documented in the literature that opioid receptors modulate a large number of physiological functions (pain perception, breathing, mood, gastrointestinal motility, etc.). Natural opiates and 4,5α-epoxymorphinan derivatives obtained by their chemical modifications, which are frequently referred to as semi-synthetic opioids, are among the most important types of opioid ligands. On the other hand, fluorinated compounds have a remarkable record in medicinal chemistry providing developmental candidates for therapeutic applications. The reasons are very similar steric impacts of hydrogen and fluorine along with the influence of substituting fluorine for hydrogen in the molecules of exogenous compounds on their lipophilicity, metabolism, conformation and other properties. This review focuses on the functionalization of 4,5α-epoxymorphinans and their derivatives via substitutions with fluorine or fluorine-containing groups in the search for improved pharmacological profile opioid ligands and 18F-containing opioid receptor radioligands for PET. These functionalizations are typically associated with substituents either at the C(3)-O, C(6)-O, and N(17) positions of the 4,5α-epoxymorphinan core or at C(7) in the thebaine based Diels-Alder type adducts. The syntheses resulted in the preparation of both single fluorinated derivatives or short sets of fluorinated derivatives and the families of fluorine-containing opioids allowing, in principle, the structure-activity relationship studies.

Dextran-Functionalized Quantum Dot Immunoconjugates for Cellular Imaging.

Brightly luminescent semiconductor quantum dots (QDs) are ideal materials for cellular imaging and analysis because of their advantageous optical properties and surface area that supports multivalent conjugation of biomolecules. An important design consideration for effective use of these materials is a hydrophilic, biocompatible surface chemistry that provides colloidal stability and minimizes nonspecific interactions with biological molecules and systems. Dextran coatings are able to satisfy these criteria. Despite frequent use of dextran coatings with other nanomaterials (e.g., iron oxide nanoparticles), there has been little development and application of dextran coatings for QDs. In this chapter, we describe methods for the synthesis and characterization of a dextran ligand for QDs, including preparation of an immunoconjugate via tetrameric antibody complexes (TAC). The utility of these immunoconjugates is demonstrated through immunofluorescent labeling and imaging of overexpressed human epidermal growth factor receptor 2 (HER2) on the surface of SK-BR3 breast cancer cells.

Recent Advances in quantitative dynamic PET imaging of neuroendocrine tumors

Dynamic positron emission tomography (PET) imaging is a standard art of molecular imaging technology for visualization and quantitative assessment of biochemical and physiopathological activity at cellular and molecular levels in humans and laboratory animals. Tracer kinetic modeling approach developed and validated in last decades is now widely used to extract parameters from dynamic PET data. In the study of neuroendocrine tumors (NETs), the kinetic parameters such as tracer uptake rate constant Ki estimated from dynamic PET with FDA approved 18 F-FDG and 68 Ga-DOTATATE tracers are suggested to improve the accuracy of NET detection, characterization, grading, staging, and predicting/monitoring NET responses to treatment including peptide receptor radionuclide therapy. The whole-body parametric Ki images generated from shortened dynamic PET using robust parametric imaging algorithm such as machine learning-based approach is potential for clinical and research in NET. In addition, dynamic PET can provide valuable information, such as biological distribution and radiation dose in tissue, in the study of new radioactive tracer in NET. It is expected that quantitative dynamic PET imaging in NET will be widely used for the imaging of somatostatin receptors and evaluation of therapeutic drugs and probes.

Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications.

Purinergic receptors play important roles in central nervous system (CNS). These receptors are involved in cellular neuroinflammatory responses that regulate functions of neurons, microglial and astrocytes. Based on their endogenous ligands, purinergic receptors are classified into P1 or adenosine, P2X and P2Y receptors. During brain injury or under pathological conditions, rapid diffusion of extracellular adenosine triphosphate (ATP) or uridine triphosphate (UTP) from the damaged cells, promote microglial activation that result in the changes in expression of several of these receptors in the brain.Imaging of the purinergic receptors with selective Positron Emission Tomography (PET) radioligands has advanced our understanding of the functional roles of some of these receptors in healthy and diseased brains. In this review, we have accumulated a list of currently available PET radioligands of the purinergic receptors that are used to elucidate the receptor functions and participations in CNS disorders. We have also reviewed receptors lacking radiotracer, laying the foundation for future discoveries of novel PET radioligands to reveal these receptors roles in CNS disorders.

Fluorescent small-molecule agonists as follicle-stimulating hormone receptor imaging tools.

Fluorescent cell surface receptor agonists allow visualization of processes that are set in motion by receptor activation. This study describes the synthesis of two fluorescent, low molecular weight ligands for the follicle-stimulating hormone receptor (FSHR), based on a dihydropyridine (DHP) agonist. We show that both BODIPY- and Cy5-conjugated DHP (m-DHP-BDP and m-DHP-Cy5) are potent FSHR agonists, able to activate receptor signalling with nanomolar potencies and to effect receptor internalisation at higher concentrations. FSHR-dependent uptake of m-DHP-Cy5 is in stark contrast to the cellular uptake of m-DHP-BDP which was efficiently internalised also in the absence of FSHR. Our results comprise a first-in-class fluorescent low molecular weight ligand for in situ FSHR imaging and pertain the potential means for targeted delivery of drugs into the endolysosomal pathway of FSHR-expressing cells.

Synthesis and Radiation Dosimetry of [<sup>68</sup>Ga]-Ga-Lys<sup>1</sup>, Lys<sup>3</sup>-DOTA-Bombesin (1,14) Antagonist for PET-Imaging, as a Potential Theragnostic Tracer in Oncology

This Bombesin (BBN), a tetradecapeptide analog of human gastrin-releasing peptide (GRP) with a high binding affinity for GRP receptors (GRPR), is over- expressed in early stages of androgen-dependent prostate carcinomas, but not in advanced stages. Therefore, there is a need to develop effective tracers for the accurate and specific detection of this disease. The objective of this study was to evaluate Lys1, Lys3-DOTA-BBN (1,14) analog with the radiolabeled positron emitter [68Ga]-Ga-BBN for receptor imaging with PET, and to determine its biodistribution and radiation dosimetry using whole-body (WB) PET scans in healthy volunteers. The highest uptake was in the pancreas, followed by urinary bladder. The critical organ was pancreas with a mean absorbed dose of 206 ± 0.7, 210 ± 0.7, 120 ± 0.9, 390.23 ± 0.6 μGy/MBq and the effective doses were estimated as 73.2 ± 0.6, 49.8 ± 0.3 μGy/MBq (women and men, respectively).

Identification of a distinct desensitisation gate in the ATP-gated P2X2 receptor

P2X receptors are trimeric ATP-gated ion channels. In response to ATP binding, conformational changes lead to opening of the channel and ion flow. Current flow can decline during continued ATP binding in a process called desensitisation. The rate and extent of desensitisation is affected by multiple factors, for instance the T18A mutation in P2X2 makes the ion channel fast desensitising. We have used this mutation to investigate whether the gate restricting ion flow is different in the desensitised and the closed state, by combining molecular modelling and cysteine modification using MTSET (2-(Trimethylammonium)ethyl methanethiosulfonate). Homology modelling of the P2X2 receptor and negative space imaging of the channel suggested a movement of the restriction gate with residue T335 being solvent accessible in the desensitised, but not the closed state. This was confirmed experimentally by probing the accessibility of T335C in the P2X2 T18A/T335C (fast desensitisation) and T335C (slow desensitisation) mutants with MTSET which demonstrates that the barrier to ion flow is different in the closed and the desensitised states. To investigate the T18A induced switch in desensitisation we compared molecular dynamics simulations of the wild type and T18A P2X2 receptor which suggest that the differences in time course of desensitisation are due to structural destabilization of a hydrogen bond network of conserved residues in the proximity of T18.

On-resin strategy to label α-conotoxins: Cy5-RgIA, a potent α9α10 nicotinic acetylcholine receptor imaging probe.

In-solution conjugation is the most commonly used strategy to label peptides and proteins with fluorophores. However, lack of site-specific control and high costs of fluorophores are recognised limitations of this approach. Here, we established facile access to grams of Cy5-COOH via a two-step synthetic route, demonstrated that Cy5 is stable to HF treatment and therefore compatible with Boc-SPPS, and coupled Cy5 to the N-terminus of α-conotoxin RgIA while still attached to the resin. Folding of the two-disulfide containing Cy5-RgIA benefitted from the hydrophobic nature of Cy5 resulting in only the globular disulfide bond isomer. In contrast, wild-type α-RgIA folded into the inactive ribbon and bioactive globular isomer under the same conditions. Labelled α-RgIA retained its ability to inhibit acetylcholine(100 μM)-evoked current reversibly with an IC50 of 5.0 nM (Hill coefficient = 1.7) for α-RgIA and an IC50 of 1.6 (Hill coefficient = 1.2) for Cy5-RgIA at the α9α10 nicotinic acetylcholine receptors (nAChRs) heterologeously expressed in Xenopus oocytes. Cy5-RgIA was then used to successfully visualise nAChRs in RAW264.7 mouse macrophage cell line. This work introduced not only a new and valuable nAChR probe, but also a new versatile synthetic strategy that facilitates production of milligram to gram quantities of fluorophore-labelled peptides at low cost, which is often required for in vivo experiments. The strategy is compatible with Boc- and Fmoc-chemistry, allows for site-specific labelling of free amines anywhere in the peptide sequence, and can also be used for the introduction of Cy3/Cy5 FRET pairs.

Ectopic insulinoma: case report

BackgroundEctopic insulinoma is a rare entity that is difficult to diagnose before surgery. This article reports two cases of ectopic insulinoma.Case presentationTwo patients manifested recurrent hypoglycemia with a typical Whipple triad. In terms of the qualitative diagnosis, the oral glucose tolerance test (OGTT) suggested a diagnosis of hyperinsulinemic hypoglycemia. However, preoperative imaging did not show a significant mass in the pancreas. In one patient, preoperative abdominal enhanced volume perfusion computed tomography (CT), somatostatin receptor imaging and 99mTc-HYNIC-TOC SPECT/CT revealed a mass with a rich blood supply anterior to the duodenum. In the other patient, preoperative enhanced CT, magnetic resonance imaging (MRI) and 68Ga-Exendin-4 PET/CT showed a mass above the spleen. After surgical removal of the tumor, both patients received a confirmed diagnosis of neuroendocrine tumors by postoperative pathology. The symptoms of hypoglycemia were relieved after surgery, and the blood glucose level was significantly increased.ConclusionEctopic insulinoma is difficult to locate before surgery. 68Ga-Exendin-4 PET/CT has a high diagnostic value. Surgical removal of the lesion is main treatment.

Branched Photoswitchable Tethered Ligands Enable Ultra-efficient Optical Control and Detection of G Protein-Coupled Receptors In Vivo

The limitations of classical drugs have spurred thedevelopment of covalently tethered photoswitchable ligands to control neuromodulatory receptors. However, a major shortcoming of tethered photopharmacology is the inability to obtain optical control with an efficacy comparable with that of the native ligand. To overcome this, we developed a family of branched photoswitchable compounds to target metabotropic glutamate receptors (mGluRs). These compounds permit photo-agonism of Gi/o-coupled group II mGluRs with near-complete efficiency relative to glutamate when attached to receptors via a range of orthogonal, multiplexable modalities. Through a chimeric approach, branched ligands also allow efficient optical control of Gq-coupled mGluR5, which we use to probe the spatiotemporal properties of receptor-induced calcium oscillations. In addition, we report branched, photoswitch-fluorophore compounds for simultaneous receptor imaging and manipulation. Finally, we demonstrate this approach invivo in mice, where photoactivation of SNAP-mGluR2 in the medial prefrontal cortex reversibly modulates working memory in normal and disease-associated states.

Molecular Imaging in Pediatric Brain Tumors.

In the last decade, several radiopharmaceuticals have been developed and investigated for imaging in vivo of pediatric brain tumors with the aim of exploring peculiar metabolic processes as glucose consumption, amino-acid metabolism, and protein synthesis with nuclear medicine techniques. Although the clinical shreds of evidence are limited, preliminary results are encouraging. In this review, we performed web-based and desktop research summarizing the most relevant findings of the literature published to date on this topic. Particular attention was given to the wide spectrum of nuclear medicine advances and trends in pediatric neurooncology and neurosurgery. Furthermore, the role of somatostatin receptor imaging through single-photon emission computed tomography (SPECT) and positron emission tomography (PET) probes, with reference to their potential therapeutic implications, was examined in the peculiar context. Preliminary results show that functional imaging in pediatric brain tumors might lead to significant improvements in terms of diagnostic accuracy and it could be of help in the management of the disease.

Kinetic analysis of [18F] altanserin bolus injection in the canine brain using PET imaging

BackgroundCurrently, [18F] altanserin is the most frequently used PET-radioligand for serotonin2A (5-HT2A) receptor imaging in the human brain but has never been validated in dogs. In vivo imaging of this receptor in the canine brain could improve diagnosis and therapy of several behavioural disorders in dogs. Furthermore, since dogs are considered as a valuable animal model for human psychiatric disorders, the ability to image this receptor in dogs could help to increase our understanding of the pathophysiology of these diseases. Therefore, five healthy laboratory beagles underwent a 90-min dynamic PET scan with arterial blood sampling after [18F] altanserin bolus injection. Compartmental modelling using metabolite corrected arterial input functions was compared with reference tissue modelling with the cerebellum as reference region.ResultsThe distribution of [18F] altanserin in the canine brain corresponded well to the distribution of 5-HT2A receptors in human and rodent studies. The kinetics could be best described by a 2-Tissue compartment (2-TC) model. All reference tissue models were highly correlated with the 2-TC model, indicating compartmental modelling can be replaced by reference tissue models to avoid arterial blood sampling.ConclusionsThis study demonstrates that [18F] altanserin PET is a reliable tool to visualize and quantify the 5-HT2A receptor in the canine brain.

Potential for imaging the high-affinity state of the 5-HT1B receptor: a comparison of three PET radioligands with differing intrinsic activity

BackgroundOver the last decade, a few radioligands have been developed for PET imaging of brain 5-HT1B receptors. The 5-HT1B receptor is a G-protein-coupled receptor (GPCR) that exists in two different agonist affinity states. An agonist ligand is expected to be more sensitive towards competition from another agonist, such as endogenous 5-HT, than an antagonist ligand. It is of interest to know whether the intrinsic activity of a PET radioligand for the 5-HT1B receptor impacts on its ability to detect changes in endogenous synaptic 5-HT density. Three high-affinity 11C-labeled 5-HT1B PET radioligands with differing intrinsic activity were applied to PET measurements in cynomolgus monkey to evaluate their sensitivity to be displaced within the brain by endogenous 5-HT. For these experiments, fenfluramine was pre-administered at two different doses (1.0 and 5.0 mg/kg, i.v.) to induce synaptic 5-HT release.ResultsA dose-dependent response to fenfluramine was detected for all three radioligands. At the highest dose of fenfluramine (5.0 mg/kg, i.v.), reductions in specific binding in the occipital cortex increased with radioligand agonist efficacy, reaching 61% for [11C]3. The most antagonistic radioligand showed the lowest reduction in specific binding.ConclusionsThree 5-HT1B PET radioligands were identified with differing intrinsic activity that could be used in imaging high- and low-affinity states of 5-HT1B receptors using PET. From this limited study, radioligand sensitivity to endogenous 5-HT appears to depend on agonist efficacy. More extensive studies are required to substantiate this suggestion.

A Survey of Molecular Imaging of Opioid Receptors.

The discovery of endogenous peptide ligands for morphine binding sites occurred in parallel with the identification of three subclasses of opioid receptor (OR), traditionally designated as μ, δ, and κ, along with the more recently defined opioid-receptor-like (ORL1) receptor. Early efforts in opioid receptor radiochemistry focused on the structure of the prototype agonist ligand, morphine, although N-[methyl-11C]morphine, -codeine and -heroin did not show significant binding in vivo. [11C]Diprenorphine ([11C]DPN), an orvinol type, non-selective OR antagonist ligand, was among the first successful PET tracers for molecular brain imaging, but has been largely supplanted in research studies by the μ-preferring agonist [11C]carfentanil ([11C]Caf). These two tracers have the property of being displaceable by endogenous opioid peptides in living brain, thus potentially serving in a competition-binding model. Indeed, many clinical PET studies with [11C]DPN or [11C]Caf affirm the release of endogenous opioids in response to painful stimuli. Numerous other PET studies implicate μ-OR signaling in aspects of human personality and vulnerability to drug dependence, but there have been very few clinical PET studies of μORs in neurological disorders. Tracers based on naltrindole, a non-peptide antagonist of the δ-preferring endogenous opioid enkephalin, have been used in PET studies of δORs, and [11C]GR103545 is validated for studies of κORs. Structures such as [11C]NOP-1A show selective binding at ORL-1 receptors in living brain. However, there is scant documentation of δ-, κ-, or ORL1 receptors in healthy human brain or in neurological and psychiatric disorders; here, clinical PET research must catch up with recent progress in radiopharmaceutical chemistry.

Orbital metastases from neuroendocrine neoplasms: clinical implications and outcomes

Neuroendocrine neoplasms (NENs) may rarely metastasise to the orbit. Published data on epidemiology, incidence and preferred treatment is limited. We present the largest cohort of symptomatic and asymptomatic NEN patients with orbital metastases and data on epidemiological parameters, symptoms as well as diagnostic/treatment modalities used. We identified patients from our internal NEN database of patients who had also undergone Gallium68-DOTATATE PET (Ga68-DOTA). The diagnosis of orbital metastatic NEN was made on somatostatin receptor imaging and confirmed on a dedicated MRI of orbits. We identified 27 patients of 994 patients evaluated with Ga68-DOTATATE PET imaging during their surveillance monitoring in our department; 15 female, average age at NEN diagnosis 53 years and orbital metastatic NEN diagnosis 59 years. The majority of NEN primaries originated from small bowel (18/27, 66.4%) or pancreas 4/27 (4/27, 14.8%). Hepatic with or without concomitant skeletal metastases were present in 23/27 (85%) of patients. Ocular symptoms and/or signs were evident in 11/27 (41%) of patients. 5/11 symptomatic patients underwent external beam radiotherapy (EBRT) resulting in complete symptoms resolution. The 5-year survival was estimated at 84.1%. Orbital metastases of NEN have a relatively low prevalence, more commonly associated with small bowel primary. Extraocular muscles are primarily affected, irrespectively of liver disease burden. Survival does not seem to be affected. EBRT is an efficacious treatment modality for both symptom relief and tumour growth control. Administration of peptide receptor radionuclide therapy may occasionally induce temporary ocular symptoms, which resolve following treatment with a short course of steroids.

New 55Co-labeled Albumin-Binding Folate Derivatives as Potential PET Agents for Folate Receptor Imaging.

Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two 55Co-labeled albumin-binding folate derivatives-[55Co]Co-cm10 and [55Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both 55Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors.

Correction of head movement by frame-to-frame image realignment for receptor imaging in positron emission tomography studies with [11C]raclopride and [11C]FLB 457

Positron emission tomography (PET) scans of imaging receptors require 60-90-min dynamic acquisition for quantitative analysis. Head movement is often observed during scanning, which hampers the reliable estimation of quantitative parameters. This study evaluated image-based motion correction by frame-to-frame realignment for PET studies with [11C]raclopride and [11C]FLB 457 acquired by an Eminence SET-3000GCT/X and investigated the effect of this correction on the quantitative outcomes. First, an optimal method for estimating motion parameters was evaluated by computer simulation. Simulated emission sinograms were reconstructed to the PET images with or without attenuation correction using a µ-map of the transmission scan. Six motion parameters were estimated frame-by-frame by registering each frame of the PET images to several types of reference images and the reliability of registration was compared. Next, in [11C]raclopride and [11C]FLB 457 studies in normal volunteers, six motion parameters for each frame were estimated by the registration method determined from the simulation results. Head movement was corrected by realigning the PET images reconstructed with a motion-included µ-map in which a mismatch between the transmission and emission scans was corrected. After this correction, time-activity curves (TAC) for the striatum or cerebral cortex were obtained and the binding potentials of the receptors (BPND) were estimated using the simplified reference tissue model. In the simulations, the motion parameters could be reliably estimated by registering each frame of the non-attenuation-corrected PET images to their early-phase frame. The motion parameters in the human studies were also obtained using the same method. After correction, a discontinuity of TACs in the striatum and cerebral cortex was remarkably improved and the BPND values in these regions increased. Compared to the motion-corrected PET images reconstructed using the measured µ-map, the images reconstructed using the motion-included µ-map did not result in a remarkable improvement of BPND in the striatum of [11C]raclopride studies, while the BPND in the cerebral cortex changed in some [11C]FLB 457 studies in which large head movement was observed. In PET receptor imaging, head movement during dynamic scans can be corrected by frame-to-frame realignment. This method is easily applicable to clinical studies and provides reliable TACs and BPND.