Synthesis and evaluation of novel bifunctional chelators based on the DATA chelator scaffold for 68Ga-positron emission tomography

• Applicant: Professor Dr. Frank Rösch, since 12/2014
• Subject Area: Pharmacy ; Inorganic Molecular Chemistry - Synthesis and Characterisation ; Nuclear Medicine, Radiotherapy, Radiobiology ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262451812

68Ga possesses a number of properties which many believe make it a very promising candidate for wider application in clinical imaging of disease and infection via PET/CT. A suitable chelator is required to stabilize the 68Ga(III) and facilitate radiolabeling of a targeting vector. The current industry incumbents for chelation of 68Ga are DOTA derivatives, which define the standard requirements in terms of stability and radiolabeling efficiency, but have limitations. Clinical application favors simple kit-type preparation protocols in which pre-administration steps are kept to a minimum. In order to realize this setup and achieve wider clinical application of 68Ga, chelators are required which radiolabel faster (<5 min) under mild conditions (298 K, pH 4-7) without compromising stability. We have developed a novel chelator series which shows excellent radiolabelling and stability characteristics that fulfill these standards. The characteristics equal and exceed those of the most promising chelators. The chelators possess both acyclic and cyclic character, representing a novel approach to chelator design for 68Ga. The combination of the wide pH range and low temperature at which radiolabelling occurs is unprecedented, and offers the potential to open 68Ga-PET to a wider range of vectors and a ready to inject kit-type radiolabelling protocol. The proposed research has the overall aims to continue the development of these chelators towards application in 68Ga-PET as bifunctional chelators, with the central idea to show the potential of the novel system. In order to carry out this objective we have outlined the necessary steps, each with its own specific objective. The chelators developed do not have the potential to conjugate to a vector in their current form. The initial aim is into introduce coupling groups onto the chelators. A series of 8 chelators has been devised, based on the 4 candidates identified in preliminary work, and initial work will focus on the synthesis and radiochemical evaluation of these chelators. Favorable candidates identified following these investigations will then be conjugated to a targeting vector (TV). A well-studied TV ([Tyr3]octreotide) has been selected so that an effective comparison can be made with the current examples. The vector is also of high commercial and clinical interest and will also be used to develop a kit-type radiolabeling protocol. The harsh conditions required for radiolabeling preclude the application of temperature and/or pH labile TVs. The chelators developed radiolabel under very mild conditions (pH 4 -7, 298 K), and therefore permit the use of labile TVs. If we can show that TV conjugation and subsequent radiolabeling can be conducted under these mild conditions, then it will be possible to utilize temperature and/or pH labile TVs within 68Ga-PET. If successful this will be the first example of kit-type radiolabeling with 68Ga, and an analogy to the highly successful 99mTc analogue.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Matthias Miederer, Ph.D.
• Ehemaliger Antragsteller: Dr. Bradley Waldron, from 12/2014 until 12/2014