The export function of the blood-brain barrier (BBB) is of increasing importance and is moving continuously into the focus of research on neurodegenerative disorders (ND). In 2011, we have described for the first time that the ABC transporter C1 (ABCC1) is exceptionally important for the export of metabolites from the brain, especially for amyloid-ß (Aß)(1). In 2019, the first ABCC1 mutation was found in a family from Phoenix (AZ, USA) with inherited clinical Fronto-temporal Lobe Degeneration (FTD) and histological AD unpublished data. ABCC1 belongs to the ABC transporter superfamily of which several members have been linked to NDs. Amongst them, a potential role of ABCA7 has been discovered in 2011 in a large NGS study (2). We hypothesize that ABC transporter function can be used to determine the impairment and remaining capacity of the BBB export in individual patients in vivo with different NDs (AD, PD, LBD, PSP)(3,4). In 2018, the drainAD phase II study (NCT03417986 a) was performed to investigate the potential role of ABC transporters (esp. ABCC1) as a new diagnostic and treatment target for AD. The study showed that patients and controls excrete Aß40 and Aß42 in a time-dependent manner according to their BBB ABCC1 function. Over the last years, partners of this consortium have performed multiple in vitro and functional animal studies to describe the function of ABCC1 / ABCA7, and we have established a new PET protocol to measure ABCC1 function in the rodent brain, which potentially can be used in patients (5). Based on this previous work, we now aim to translate our ABCC1 PET protocol to AD patients to assess whether cerebral ABCC1 function is impaired in comparison to age-matched healthy control subjects and to investigate the relevance of ABCC1 for the diagnostics of functional BBB-deficiency, which will allow better classification of patient groups. In parallel, we will extend our efforts to ABCA7. The segregation of disease diagnoses/sub-diagnoses will enable targeted treatment studies for those patients that show functional deficiency. Moreover, we also aim on the stratification of patient populations for preventive and treatment interventions. One essential part of the project is a patient study to assess ABCC1 function using a new PET protocol (6). Another important part is the development of novel PET radiotracers for functional imaging for ABCA7. Thus, we will perform in vitro and in vivo investigations by using human and mouse cell culture BBB models (iPSCs based and with specific knockout endothelia), humanised mouse models (humABCC1 (7), humABCA7 (unpublished)), chemical synthesis of new ABCA7 probes, morphological/toxicology analyses, ssNMR, radiolabelling methods, and animal PET imaging. The humanised mouse models available to us are inducible and worldwide unique. These will enable us to assess the specific function of the human transport molecules A7 and C1 in different settings. Our main goal is to develop new PET imaging protocols for the assessment of BBB deficiency with regard to ABCA7 and ABCC1 function in patients with NDs. (a) https://clinicaltrials.gov/ct2/show/NCT03417986 (1) Krohn, M. (2011) J Clin Invest 121, 3924-3931, PMID21881209 (2) Hollingworth, P. (2011) Nat Genet 43, 429-435, PMID21460840 (3) Bartels, A. L. (2009) Neurobiol Aging 30, 1818-1824,18358568 (4) Bartels, A. L. (2008) J Neural Transm (Vienna) 115, 1001-1009,PMID18265929 (5) Zoufal, V. (2019) J Cereb Blood Flow Metab, 271678X19854541 PMID31195936 (6) Zoufal, V. (2019) Mol Imaging Biol 21, 306-316, PMID29942989 (7) Krohn, M. (2019) Mol Pharmacol 96, 138-147, PMID31189668