Introduction of a fatty acid chain modification to prolong circulatory half-life of a radioligand towards glucose-dependent insulinotropic polypeptide receptor.

BACKGROUND: The beneficial role of glucose-dependent insulinotropic polypeptide receptor (GIPR) in weight control and maintaining glucose levels has led to the development of several multi-agonistic peptide drug candidates, targeting GIPR and glucagon like peptide 1 receptor (GLP1R) and/or the glucagon receptor (GCGR). The in vivo quantification of target occupancy by these drugs would accelerate the development of new drug candidates. The aim of this study was to evaluate a novel peptide (GIP1234), based on previously reported ligand DOTA-GIP-C803, modified with a fatty acid moiety to prolong its blood circulation. It would allow higher target tissue exposure and consequently improved peptide uptake as well as in vivo PET imaging and quantification of GIPR occupancy by novel drugs of interest. METHOD: A 40 amino acid residue peptide (GIP1234) was synthesized based on DOTA-GIP-C803, in turn based on the sequences of endogenous GIP and Exendin-4 with specific amino acid modifications to obtain GIPR selectivity. A palmitoyl fatty acid chain was furthermore added at Lys14 via a glutamic acid linker to prolong its blood circulation time by the interaction with albumin. GIP1234 was conjugated with a DOTA chelator at the C-terminal cysteine residue to achieve 68Ga radiolabeling. The resulting PET probe, [68Ga]Ga-DOTA-GIP1234 was evaluated for receptor binding specificity and selectivity using HEK293 cells transfected with human GIPR, GLP1R, or GCGR. Blocking experiments with tirzepatide (2 µM) were conducted using huGIPR HEK293 cells to investigate binding specificity. Ex vivo and in vivo organ distribution of [68Ga]Ga-DOTA-GIP1234 was studied in rats and a pig in comparison to [68Ga]Ga-DOTA-C803-GIP. Binding of [68Ga]Ga-DOTA-GIP1234 to albumin was assessed in situ using polyacrylamide gel electrophoresis (PAGE). The stability was tested in formulation buffer and rat blood plasma. RESULTS: [68Ga]Ga-DOTA-GIP1234 was synthesized with non-decay corrected radiochemical yield of 88 ± 3.7 % and radiochemical purity of 97.8 ± 0.8 %. The molar activity for the radiotracer was 8.1 ± 1.1 MBq/nmol. [68Ga]Ga-DOTA-GIP1234 was stable and maintained affinity to huGIPR HEK293 cells (dissociation constant (Kd) = 40 ± 12.5 nM). The binding of [68Ga]Ga-DOTA-GIP1234 to huGCGR and huGLP1R cells was insignificant. Pre-incubation of huGIPR HEK293 cell sections with tirzepatide resulted in the decrease of [68Ga]Ga-DOTA-GIP1234 binding by close to 90 %. [68Ga]Ga-DOTA-GIP1234 displayed slow blood clearance in pigs with SUV = 3.5 after 60 min. Blood retention of the tracer in rat was 2-fold higher than that of [68Ga]Ga-DOTA-C803-GIP. [68Ga]Ga-DOTA-GIP1234 also demonstrated strong liver uptake in both pig and rat combined with decreased renal excretion. The concentration dependent binding of [68Ga]Ga-DOTA-GIP1234 to albumin was confirmed in situ by PAGE. CONCLUSION: [68Ga]Ga-DOTA-GIP1234 demonstrated nanomolar affinity and selectivity for huGIPR in vitro. Addition of a fatty acid moiety prolonged blood circulation time and tissue exposure in both rat and pig in vivo. However, the liver uptake was also increased which may make PET imaging of abdominal tissues such as pancreas challenging. The investigation of the influence of fatty acid moiety on the biological performance of the peptide ligand paved the way for further rational design of GIPR ligand analogues with improved characteristics.

Type A Aortic Dissection Masquerading as an Inferior Myocardial Infarction.

Type A aortic dissection is a life-threatening condition with a wide range of clinical manifestations. Dissection can sometimes mimic an acute myocardial infarction due to similar presenting symptoms and initial clinical investigations. We report the case of a 52-year-old male who presented with an inferior ST-segment elevation myocardial infarction with two drug-eluting stents inserted as a stabilizing intervention prior to surgical repair of an acute aortic dissection.

COVID-19 related mortality in post-operative cardiac surgical patients.

BACKGROUND: COVID-19 has caused a global pandemic of unprecedented proportions. Elective cardiac surgery has been universally postponed with only urgent and emergency cardiac operations being performed. The National Health Service in the United Kingdom introduced national measures to conserve intensive care beds and significantly limit elective activity shortly after lockdown. CASE PRESENTATION: We report two cases of early post-operative mortality secondary to COVID-19 infection immediately prior to the implementation of these widespread measures. CONCLUSION: The role of cardiac surgery in the presence of COVID-19 is still very unpredictable and further studies on both short term and long term outcomes are warranted.

An alternative surgical approach to subclavian and innominate stenosis: a case series.

We report three cases of symptomatic stenosis of the great vessels or supra-aortic trunks successfully treated surgically with aorto-subclavian and aorto-innominate bypass. Two were performed via manubriotomy and a third case via standard median sternotomy because of concomitant coronary revascularisation. There was complete symptomatic relief on follow-up, and radiological imaging confirmed good flow in the grafts and post-stenotic arteries.

3f prosthesis aortic cusp replacement: implantation technique and early results.

Stentless aortic bioprostheses have been successfully used for over a decade. The 3f bioprosthesis is a new equine pericardial stentless valve, unique in its tubular design, preserving the native aortic sinuses post-implant. Forty-six consecutive aortic valve replacements with the 3f bioprosthesis were performed between June 2003 and January 2005. The patients were prospectively assessed and echocardiography was performed at 6 months, 12 months, and annually thereafter. The median follow-up was 2.1 + or - 0.9 years. There was one early and 4 late deaths; none were valve-related. The 2-year mean transvalvular gradient was 8.8 + or - 3.8 mm Hg, the mean echocardiographic aortic regurgitation grade was 0.4 + or - 0.7 (grade 1 being trivial). Echocardiographic sizing of the aortic annulus before surgery accurately predicted prosthesis size. The 3f bioprosthesis is easy to implant. Early clinical results are favorable, with hemodynamic profiles consistent with those of other stentless prostheses. Longer follow-up is required to confirm its durability.