Towards Facile Radiolabeling and Preparation of Gallium-68-/Bismuth-213-DOTA-[Thi8, Met(O2)11]-Substance P for Future Clinical Application: First Experiences

Janine Suthiram; Thomas Ebenhan; Biljana Marjanovic-Painter; Mike M Sathekge; Jan Rijn Zeevaart

doi:10.3390/pharmaceutics13091326

Towards Facile Radiolabeling and Preparation of Gallium-68-/Bismuth-213-DOTA-[Thi⁸, Met(O₂)¹¹]-Substance P for Future Clinical Application: First Experiences

Pharmaceutics. 2021 Aug 25;13(9):1326. doi: 10.3390/pharmaceutics13091326.

Authors

Janine Suthiram^{1

2}, Thomas Ebenhan^{1

2

3}, Biljana Marjanovic-Painter¹, Mike M Sathekge^{2

3

4}, Jan Rijn Zeevaart^{1

3

5}

Affiliations

¹ Radiochemistry, The South African Nuclear Energy Corporation (Necsa), Brits 0240, South Africa.
² Department of Nuclear Medicine, University of Pretoria, Pretoria 0001, South Africa.
³ Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria 0001, South Africa.
⁴ Department of Nuclear Medicine, Steve Biko Academic Hospital, University of Pretoria, Pretoria 0001, South Africa.
⁵ Preclinical Drug Development Platform, Department of Science and Technology, North West University, Potchefstroom 2520, South Africa.

Abstract

Substance P (SP) is a small peptide commonly known as a preferential endogenous ligand for the transmembrane neurokinin-1 receptor. Nuclear Medicine procedures currently involve radiolabeled SP derivatives in peptide radioligand endotherapy of inoperable glioblastoma. Promising clinical results sparked the demand for facile production strategies for a functionalized 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi⁸, Met(O₂)¹¹]-SP to allow for rapid Gallium-68 or Bismuth-213 complexation. Therefore, we provide a simple kit-like radiotracer preparation method that caters for the gallium-68 activity eluted from a SnO₂ generator matrix as well as preliminary results on the adaptability to produce [²¹³Bi]Bi-DOTA-[Thi⁸, Met(O₂)¹¹]SP from the same vials containing the same starting material. Following a phase of radioanalysis for complexation of gallium-68 to DOTA-[Thi⁸, Met(O₂)¹¹]SP and assessing the radiolabeling parameters, the vials containing appropriate kit-prototype material were produced in freeze-dried batches. The facile radiolabeling performance was tested and parameters for future human application were calculated to meet the criteria for theranostic loco-regional co-administration of activity doses comprising [⁶⁸Ga]Ga-DOTA-[Thi⁸, Met(O₂)¹¹]SP mixed with [²¹³Bi]Bi-DOTA-[Thi⁸, Met(O₂)¹¹]SP. [⁶⁸Ga]Ga-DOTA-[Thi⁸, Met(O₂)¹¹]SP was prepared quantitatively from lyophilized starting material within 25 min providing the required molar activity (18 ± 4 GBq/µmol) and activity concentration (98 ± 24 MBq/mL), radiochemical purity (>95%) and sustained radiolabeling performance (4 months at >95% LE) as well as acceptable product quality (>95% for 120 min). Additionally, vials of the same starting materials were successfully adapted to a labeling strategy available for preparation of [²¹³Bi]Bi-DOTA-[Thi⁸, Met(O₂)¹¹]SP providing sufficient activity for 1-2 human doses. The resultant formulation of [⁶⁸Ga]Ga-/[²¹³Bi]Bi-DOTA-[Thi⁸, Met(O₂)¹¹]SP activity doses was considered of adequate radiochemical quality for administration. This investigation proposes a simple kit-like formulation of DOTA-[Thi⁸, Met(O₂)¹¹]SP-a first-line investigation into a user friendly, straightforward tracer preparation that would warrant efficient clinical investigations in the future. Quantitative radiolabeling was accomplished for [⁶⁸Ga]Ga-DOTA-[Thi⁸, Met(O₂)¹¹]SP and [²¹³Bi]Bi-DOTA-[Thi⁸, Met(O₂)¹¹]SP preparations; a key requirement when addressing the specific route of catheter-assisted co-injection directly into the intratumoral cavities.

Keywords: 68Ge/68Ga generator; DOTA; DOTA-Substance P; [213Bi]Bi-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi8, Met(O2)11]-Substance-P; [68Ga]Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi8, Met(O2)11]-Substance-P; gallium-68; kit preparation.