New Long-Acting [⁸⁹Zr]Zr-DFO GLP-1 PET Tracers with Increased Molar Activity and Reduced Kidney Accumulation

Abstract

Positron emission tomography (PET) imaging is used in drug development to noninvasively measure biodistribution and receptor occupancy. Ideally, PET tracers retain target binding and biodistribution properties of the investigated drug. Previously, we developed a zirconium-89 PET tracer based on a long-circulating glucagon-like peptide 1 receptor agonist (GLP-1RA) using desferrioxamine (DFO) as a chelator. Here, we aimed to develop an improved zirconium-89-labeled GLP-1RA with increased molar activity to increase the uptake in low receptor density tissues, such as brain. Furthermore, we aimed at reducing tracer accumulation in the kidneys. Introducing up to four additional Zr-DFOs resulted in higher molar activity and stability, while retaining potency. Branched placement of DFOs was especially beneficial. Tracers with either two or four DFOs had similar biodistribution as the tracer with one DFO in vivo, albeit increased kidney and liver uptake. Reduced kidney accumulation was achieved by introducing an enzymatically cleavable Met-Val-Lys (MVK) linker motif between the chelator and the peptide.

Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic

“…This research utilized a cleavable linker which could be recognized and cleaved by angiotensin-converting enzyme (ACE) or neprilysin to reduce kidney uptake of radio­labeled peptides and proteins. , Gustafsson et al describe the in vitro and in vivo evaluation of new long-lasting glucagon-like peptide 1 (GLP-1) derivatives labeled with Zr-89. Reduced kidney accumulation was achieved by introducing an enzymatically cleavable motif between the chelator and the peptide …”

Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic

“…Reduced kidney accumulation was achieved by introducing an enzymatically cleavable motif between the chelator and the peptide. 30 The work of Sutcliffe et al combines the integrin α v β 6 binding peptide (α v β 6 -BP) with the cytotoxic agent monomethyl auristatin E (MMAE) with the goal to increase efficacy while reducing peripheral toxicity. This peptide−drug conjugate (PDC) was designed to contain a metal chelator (DOTA), enabling radiolabeling with PET radionuclides, thus demonstrating utility as a theranostic, and a protease-cleavable linker which is hydrolyzed by an enzyme that is upregulated in cancer cells, resulting in the release of MMAE.…”

Using PET imaging as tool to unravel drug response variability in type 2 diabetes

“…But, for example, for drugs acting in the central nervous system, the exposure at the target site may differ from plasma, because their distribution is dependent on the functionality of specific transporters due to the presence of the blood brain barrier. 44 For SGLT2 inhibiters, the target site is the proximal tubule in the kidney, where they bind to the SGLT2, most likely from the luminal side. 45 ARBs target the angiotensin II type 1 receptor (AT 1 R), in kidneys expressed in the glomeruli, proximal and distal tubules, and afferent and efferent arterioles.…”

“…Blood oxygenation level-dependent MRI (BOLD-MRI) uses the difference in magnetic properties of oxygenated versus deoxygenated hemoglobin. 44 Method validation has been performed in pig and the reproducibility has been assessed in healthy volunteers and patients with CKD. 24,[45][46][47] The first BOLD-MRI studies evaluating renal oxygenation showed conflicting results.…”

“…Dit maakt duidelijk dat deze methode van het maken van een tracer van een medicijn een heel specifiek onderzoeksgebied is, en ook dat deze aanpak misschien niet mogelijk is voor elk medicijn. [42][43][44] Concluderend heeft PET onderzoek met [ 11 C]Telmisartan en [ 18 F]Canagliflozine de potentie om een belangrijke bijdrage te leveren aan het vergroten van onze kennis over RAASen SGLT2 remmers. Het kan namelijk de samenhang tussen dosering, concentratie in het bloed, verspreiding naar de nieren, interactie met de receptor en het effect van het medicijn onderzoeken.…”