Synaptic pathology is associated with several brain disorders, thus positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) using the radioligand [11C]UCB-J may provide a tool to measure synaptic alterations. Given the pivotal role of mouse models in understanding neuropsychiatric and neurodegenerative disorders, this study aims to validate and characterize [11C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examined kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metabolism. Regional TACs during baseline showed rapid uptake of [11C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. VT (IDIF) values estimated with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, p < 0.0001), with 1TCM performing better than 2TCM for K1 (IDIF). A scan duration of 60 min was sufficient for reliable VT (IDIF) and K1 (IDIF) estimations. In vivo metabolism of [11C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [11C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic density in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.

As unidades litológicas da região noroeste do Estado do Rio de Janeiro e sul do Espírito Santo estão situadasno segmento setentrional da Faixa Ribeira. O conhecimento da estruturação tectônica deste segmento dafaixa possibilita sua correlação com o segmento sul da Faixa Araçuaí. A compartimentação tectônica da FaixaRibeira, estabelecida no seu setor central, compreende quatro terrenos tectono-estratigráficos: Ocidental,Oriental, Paraíba do Sul/Embú e Cabo Frio. Os dois primeiros terrenos são separados por uma zona decisalhamento complexamente redobrada (Limite Tectônico Central- LTC) com mergulhos subverticais amoderados para NW na porção centro-sul fluminense, e mergulhos para SE na porção noroeste fluminensee sul capixaba. O limite basal dos terrenos Cabo Frio e Paraíba do Sul/Embú é representado por uma zona decisalhamento de baixo ângulo, com mergulhos para SE e NW. Os três primeiros terrenos foram amalgamadosentre ca. 600 e 570 Ma, enquanto que Terreno Cabo Frio foi acrescionado ao final da colagem orogênica, em ca.530-510 Ma. Estes terrenos representariam paleoplacas convergentes durante a formação do supercontinenteGondwana na transição Neoproterozóico/Cambriano. O Terreno Ocidental corresponderia à paleoplacainferior (Placa Sanfranciscana), e o Terreno Oriental à placa superior, na qual se instalou o arco magmáticoresponsável pela colisão Arco/Continente. Para leste, por trás do Terreno Oriental, o fechamento do espaçoback-arc resultou na colisão com a paleoplaca do Terreno Cabo Frio. O Terreno Ocidental é representadopelo Domínio Tectônico Juiz de Fora, que integra rochas paleoproterozóicas do Complexo Juiz de Fora euma seqüência metassedimentar neoproterozóica conhecida como Megasseqüência Andrelândia. O TerrenoParaíba do Sul aflora como uma klippe sinformal complexamente dobrada sobre o Terreno Ocidental. ÉGEONOMOS 15(1): 67 - 79, 200768constituído por ortognaisses paleoproterozóicos do Complexo Quirino e por um conjunto metassedimentarrico em intercalações de mármores dolomíticos e de idade ainda incerta, denominado de Complexo Paraíba doSul. O Terreno Oriental, que contem as rochas geradas em ambientes de arco magmático e metassedimentosneoproterozóicos, foi subdividido na região noroeste fluminense em três domínios estruturais distintos: a)o Domínio Cambuci, em posição basal, compreende uma seqüência metavulcano-sedimentar com lentesde mármore e ortognaisses calcioalcalinos com ambiência tectônica de arco magmático; b) o DomínioCosteiro é constituído por metassedimentos pelíticos em fácies granulito a anfibolito alto, com intercalaçõesde quartzitos impuros intrudidos por ortognaisses e metagabros do Arco Magmático Rio Negro (ca. 790 a620 Ma); c) a Klippe de Italva aflora sobre o Domínio Costeiro e compreende um conjunto metavulcanosedimentarcom mármores calcíticos, anfibolitos (ca. 840 Ma) e paragnaisses com provável contribuiçãovulcânica. O Terreno Cabo Frio não aflora na região noroeste fluminense, sendo limitado por uma falharúptil de direção NWW-SEE na região de Macaé. A comparação entre este segmento da Faixa Ribeira e osegmento meridional da Faixa Araçuaí, ainda em andamento, sugere a continuidade lateral do Domínio Juiz deFora para o denominado Domínio Externo e o prolongamento dos Domínios Cambuci e Costeiro do TerrenoOriental para o Domínio Interno da Faixa Araçuaí. Neste sentido, os metassedimentos do Grupo Rio Doce eos ortognaisses equivalentes ao Tonalito Galiléia poderiam ser correlacionados às unidades litoestratigráficasdo Domínio Cambuci, enquanto os metassedimentos de alto grau atribuídos ao Complexo Paraíba do Sul eortognaisses da porção leste do Estado do Espírito Santo poderiam ser correlatos às unidades do DomínioCosteiro, incluindo o arco Rio Negro. Restam ainda dois domínios com aloctonia completa, ou seja, comuma superfície de descolamento em sua base e sem ligação com sua raiz, que seriam representadas pelasklippen Paraíba do Sul e Italva, que possuem posicionamento paleogeográfico ainda incerto. ABSTRACT: The northern sector of the Ribeira Belt is located in parts of the states of Rio de Janeiro and Espírito Santo,and its tectonic organization helps to understand the correlations between the Ribeira and Araçuaí belts.Four tectono-stratigraphic terrains have been already described in the central sector of the Ribeira Belt:Occidental, Oriental, Paraíba do Sul/Embú and Cabo Frio. The Central Tectonic Boundary (CTB), a foldedshear zone, separates the Occidental and Oriental terrains. It changes from a low to high angle NW dippingto a low angle SE dipping surface, from the Central to Northern Ribeira Belt. Subhorizontal to verticallyfolded shear zones that dips to SE or NW are interpreted as base thrusts of the Cabo Frio and Paraíba doSul/Embú terrains. The amalgamation of the first three terrains occurred between 600 and 570 Ma, whilethe Cabo Frio terrain collided during 530 to 510 Ma, at the end of the orogenic collage. These terrains areinterpreted as colliding paleoplates involved in the Neoproterozoic/Cambrian Gondwana formation: a) theOccidental terrain was the lower plate (São Francisco Paleoplate); b) the Oriental terrain was the upper platewith the magmatic arc that acted as a collisional backstop; c) the closure of the back-arc basin to the eastresulted in the final collision of the Cabo Frio paleoplate/terrain. In the studied areas, the Occidental Terrainis represented only by the Juiz de Fora tectonic domain which comprises palaeoproterozoic granulites ofthe Juiz de Fora Complex and a neoproterozoic metasedimentary sequence (Andrelândia Megasequence).The Paraíba do Sul/Embú Klippe is structured as a noncylindrical sinform over the Occidental Terrain. Itcontains palaeoproterozoic orthogneisses of the Quirino Complex and a carbonatic-pelitic metasedimentarysequence (Paraíba do Sul Group) with uncertain depositional age. Arc-related meta-plutonic, volcanic andsedimentary rocks constitute the Oriental terrain. At the NW region of the Rio de Janeiro State, it can bedivided into three tectonic domains: a) the Cambuci Domain, with calc-alkaline metaplutonic rocks and acarbonatic to pelitic meta- vulcanosedimentary sequence; b) the Costeiro Domain, comprising the Rio NegroMagmatic Arc (790 a 620 Ma); c) the Italva Klippe which overlays the Costeiro Domain and consists of acarbonatic and metamafic volcano sedimentary sequence dated at 840 Ma, with plutonic fragments of theRio Negro Arc. The Cabo Frio terrain is limited, to the west, by a NNW-SSE trending brittle shear zonenear Macaé town and probably do not extends into the Araçuaí Belt. The correlation between the northernsection of the Ribeira Belt and the southern section of the Araçuaí Belt, still at work, suggests a link betweenthe Juiz de Fora Domain and the External Domain of the Araçuaí Belt, and also between the Cambuci andCosteiro domains and the Internal Domain of the Araçuaí Belt. The Cambuci Unit and the calc-alkalinemetaplutonic rocks of the Cambuci Domain can be correlated, respectively, to the Rio Doce Group and theGaliléia Tonalite in the Araçuaí Belt. The high-grade metasediments and orthogneisses of the Costeiro Domain(including the Rio Negro Complex) can be easily followed northward up to the kinzigites and high-grademetassediments at eastern Espírito Santo State, formerly included in the Paraíba do Sul Complex. Availablegeological data does not yield reliable information about the paleogeographic context of the allochtonousParaíba do Sul/Embu and the Italva klippe.

Purpose: This study aimed at investigating binding specificity, suitability of reference regionbased kinetic modelling, and pharmacokinetics of the metabotropic glutamate receptor 1 (mGluR1) radioligand [ 11 C]ITDM in mice. Procedures: We performed in vivo blocking as well as displacement of [ 11 C]ITDM during positron emission tomography (PET) imaging using the specific mGluR1 antagonist YM-202074. Additionally, we assessed in vitro blocking of [ 3 H]ITDM at two different doses of YM-202074. As an alternative to reference region models, we validated the use of a noninvasive image-derived input function (IDIF) compared to an arterial input function measured with an invasive arteriovenous (AV) shunt using a population-based curve for radiometabolite correction and characterized the pharmacokinetic modelling of [ 11 C]ITDM in the mouse brain. Finally, we also assessed semi-quantitative approaches. Results: In vivo blocking with YM-202074 resulted in a decreased [ 11 C]ITDM binding, ranging from − 35.8 ± 8.0 % in pons to − 65.8 ± 3.0 % in thalamus. Displacement was also markedly observed in all tested regions. In addition, in vitro [ 3 H]ITDM binding could be blocked in a dosedependent manner. The volume of distribution (V T) based on the noninvasive IDIF (V T (IDIF)) showed excellent agreement with the V T values based on the metabolite-corrected plasma input function regardless of the metabolite correction (r 2 9 0.943, p G 0.0001). Two-tissue compartmental model (2TCM) was found to be the preferred model and showed optimal agreement with Logan plot (r 2 9 0.960, p G 0.0001). A minimum scan duration of 80 min was required for proper parameter estimation. SUV was not reliable (r 2 = 0.379, p = 0.0011), unlike the SUV ratio to the SUV of the input function, which showed to be a valid approach. Conclusions: No suitable reference region could be identified for [ 11 C]ITDM as strongly supported by in vivo and in vitro evidence of specific binding in all brain regions. However, by

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin ( HTT ) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) tract. Whereas several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, methods to visualize mHTT protein species in the living brain are lacking. Here, we demonstrate the development and characterization of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11 C ([ 11 C]CHDI-180R) allowed noninvasive monitoring of mHTT pathology in the brain and could track region- and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression in a rodent model. We further showed that in these animals, therapeutic agents that lowered mHTT in the striatum had a functional restorative effect that could be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.

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