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Accelerating the discovery and development of neurotracers via high-throughput radiochemistry

Award Number: R01EB032264
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Accelerating the discovery and development of neurotracers via high-throughput radiochemistry - PROJECT SUMMARY/ABSTRACT The continuous discovery of new biological targets presents opportunities to dramatically improve our understanding of diseases and normal function and provides new avenues for treatment. In vivo imaging of these targets via positron-emission tomography (PET) is an especially powerful tool to understand the initiation and progression of disease and to aid in the development of novel therapeutics. The major benefits of PET are the very high sensitivity (enabling imaging of rare targets such as neuroreceptors without saturating them), and the ability to image deep tissues (which provides translatability from preclinical research to later clinical use). But the development of useful and validated tracers can take years or decades. A significant limiting factor is the complexity and cost of radiochemistry, and the difficulty in using current technologies to optimize synthesis conditions – a key step toward achieving reliable production with sufficient yield to support initial imaging studies. Slow throughput and high reagent and isotope consumption mean that optimization studies are very expensive and time-consuming, and thus such studies tend to be very limited and are unlikely to find globally optimal conditions. These limitations also create pressures in other aspects of new probe development, e.g., significant efforts are made to reduce the number of “hits” so only a very small number of compounds are labeled and studied via in vitro and ex vivo assays and in vivo imaging. However, this selection process is imperfect as it sometimes leads to the pursuit of dead-ends while it excludes promising candidates. To more rapidly leverage preclinical and clinical imaging of new biological targets, the radiochemistry field is in urgent need of new tools to improve the tracer discovery and development process. Our proposed solution is the development of high-throughput radiochemistry methods. Arrays of droplet reactions have recently been introduced as a way to rapidly perform dozens of reactions in parallel from a single batch of radioisotope, with total reagent consumption of those reactions similar to a single batch on a conventional system. Furthermore, the droplet reactions can readily be scaled to quantities for preclinical or even clinical imaging. These methods could be used to efficiently explore a vast reaction parameter space in a matter of days (instead of weeks to months), or they could be used to label dozens of candidate compounds in parallel to perform screening based on the most relevant metric: in vivo properties. While these reaction arrays, operated using manual pipetting, have revealed the benefits and potential of high-throughput radiochemistry, this new technology requires significant further development and automation to increase safety and speed, and reduce the chance for human error. We propose to (1) integrate in situ radiation detectors to quantify the radioactivity at various stages of each reaction, (2) integrate a method to automatically sample the reactions for analysis (radio-TLC or radio-UPLC), and (3) use high-throughput methods to optimize the synthesis of 5 neurotracers that currently have low yield, develop at least one novel tracer, and develop best practices for high-throughput optimization in radiochemistry.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $596,699 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	2/19/2025	NON-COMPETING CONTINUATION	$596,699
														Subtotal = $596,699

Issue Date FY: 2024 ( Subtotal = $734,592 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	002	3	6/26/2024	SUPPLEMENT FOR EXPANSION	$84,853
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	3	5/27/2024	NON-COMPETING CONTINUATION	$53,040
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10920 WILSHIRE BLVD STE 500	LOS ANGELES	CA	90024	LOS ANGELES	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	2/29/2024	NON-COMPETING CONTINUATION	$596,699
														Subtotal = $734,592

Issue Date FY: 2023 ( Subtotal = $662,998 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	2/22/2023	NON-COMPETING CONTINUATION	$662,998
														Subtotal = $662,998

Issue Date FY: 2022 ( Subtotal = $662,998 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	6/6/2022	NEW	$662,998
														Subtotal = $662,998

Grand Total All Awards = $2,657,287

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Accelerating the discovery and development of neurotracers via high-throughput radiochemistry

Award Number: R01EB032264

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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