Page 136 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis

Chapter 6
these albumin binders increased blood residence time, in tumor bearing mice, with a couple of hours. Although their tracer with Asp-4-(p-iodophenyl)butyric acid as albumin binder has a more modest increase of circulation time than our [177Lu]Lu-Albutate-1 (t1/2 ~ 3 vs 27 h), no increase in therapeutic index was seen.
Műller et al performed pre-clinical research [19] and found that adding the 4-(p-iodophenyl) butyric acid albumin-binding entity to a DOTA-folate improved the overall tissue distribution significantly. To further reduce renal accumulation of radioactivity [26] the same group also made 2 other albumin- binding radiofolates to further restrict renal accumulation [27]. A longer spacer consisting of a PEG-11 entity and a short alkane chain between the albumin-binding moiety and folic acid [18] was investigated. Data shows that the spacer entity between folic acid and the albumin binder was of critical importance with regard to the tissue distribution profile of the radiotracer, with a preference for a shorter spacer entity.
The same group studied 3 different prostate-specific membrane antigen (PSMA) targeting radioligands with a 4-(p-iodophenyl)-based albumin binder, the same as applied in our study. They developed three ligands with variations in linker length [28]. All radioligands showed an enhanced circulation time and a higher tumor uptake, but the one with the shortest linker length emerged as the most favorable candidate of all ligands, which might be promising for our approach as well.
In another study [29] albumin binders were based on a stronger albumin- binding 4-(p-iodophenyl)-moiety and a weaker albumin-binding p-(tolyl)- moiety. The weaker albumin-binder affected tumor uptake, blood retention time and the therapeutic index more positively, pointing out to be more suited as an albumin binder with an optimized tissue distribution profile.
To overcome the high radiation dose to the body it might be possible to use a long circulating tracer as a candidate for pre-targeting [30, 31]. This could for example be JR-11, which is an antagonist for the SSTR2 receptor [32, 33], coupled to albumin. First, the tracer will accumulate at the tumor site. Then you wait until the rest of the tracer is largely cleared form the blood pool. Then the second step, a small radiolabeled peptide, can be injected.
134